omia_id molecular_description mapping_info species
OMIA:000439 "Legrand et al. (2014) ""identified a recessive c.433_434delAT frameshift deletion in FGF5, present in Poitou and three other donkey breeds and a recessive nonsense c.245G > A substitution, present in Poitou and four other donkey breeds. The frameshift deletion was associated with the long-hair phenotype in Poitou donkeys when present in two copies (n = 31) or combined with the nonsense mutation (n = 4). The frameshift deletion led to a stop codon at position 159 whereas the nonsense mutation led to a stop codon at position 82 in the FGF5 protein. In silico, the two truncated FGF5 proteins were predicted to lack the critical β strands involved in the interaction between FGF5 and its receptor, a mandatory step to inhibit hair growth.""" 9793
OMIA:001864 "Extensive and detailed clinical, histological, electron micrographical and protein immunomapping investigations (the latter showing a lack of plakophilin-1 (PKP1) in affected dogs) by Olivry et al. (2012) suggested a strong candidate gene. Sequencing of the exons and exon-intron junctions of the canine PKP1 gene revealed a causative mutation: ""a G-to-C conversion at the IVS1 splice donor site of the first intron . . . , which was homozygous in affected puppies and heterozygous in their parents available for testing. This conversion results in a destruction of the intronic splice donor site resulting in a continual read through to a premature stop codon located nine codons downstream from the mutation . . . . As a consequence, the mutated protein is predicted to be truncated and composed of 75 instead of 749 aminoacids."" Using the genetic variant nomenclature of 2015, the causative variant can be decribed as c.202+1G>C. (thanks to Hamutal Mazrier for alerting FN to this discovery)" 9615
OMIA:002045 "Chew et al. (2017; Animal Genetics) excluded 53 candidate loci in a screen of WGS data from a Hungarian Puli family trio (normal sire, normal dam and proband offspring) and from an affected half sib of the proband.
By combining the above WGS data with SNP genotyping data from the CanineHD BeadChip array, Chew et al. (2017; G3) identified a likely causal variant as ""A single nonsense SNP in exon 2 of BBS4 (c.58A>T, p.Lys20*) . . . [that] . . . segregates perfectly with progressive retinal atrophy in the Hungarian Puli."" ""This mutation encodes a premature stop codon which is expected to result in complete loss of function of the BBS4 protein""." 9615
OMIA:000862 "Meijerink et al. (2000) provided strong evidence that the previously-described base substitution at nucleotide 307 of the FUT1 gene (see Marker section above), which is a G to A missense mutation, resulting in 103 (Ala-->Thr), is the key mutation in enabling ""adhesion of ECF18 bacteria to small intestinal mucosa""." "Using ""14 blood group systems, 11 biochemical polymorphisms and the polymorphism at nucleotide 1843 of the RYR1 locus"", Vogeli et al. (1996) mapped ECF18R to the middle of the hal (RYR1) linkage group on chromosome SSC6. Noting that one of the genes in this linkage group is the S gene (for suppression of blood group system A), and that the likely human homologue of S is blood group system I-I (whose locus encodes the enzyme alpha-fucosyltransferase, FUT), Meijerink et al. (1997) isolated porcine homologues of FUT, and showed that they mapped to the same location as the S gene, i.e. the recombination fraction between FUT and S is zero." 9825
OMIA:000263 "The causative mutation is a G to A transition (c.118G>A; p.E40K) in exon 2 of SOD1. All affected dogs tested were homozygous mutant. However, some homozygous mutant dogs had no signs of degenerative myelopathy, which suggests incomplete penetrance or other causative loci (Awano et al., 2009). The mutation is hypothesized to lead to SOD1 aggregation, as cytoplasmic inclusions in affected dogs stain with anti-SOD1 antibodies (Awano et al., 2009).
A second causal mutation (c.52A>T; p.Thr18Ser) in the same gene, in a Bernese Mountain Dog, was reported by Wininger et al. (2011).
Having genotyped 408 Bernese Mountains dogs for both the above mutations, Pfahler et al. (2014) reported that ""The c.118G>A mutation was heterozygous in 188 (46.1%) and homozygous in 27 (6.6%) BMD (Table S2). The c.52A>T mutation was heterozygous in 65 (15.9%) and homozygous in two (0.5%) dogs. Twenty-two of the animals had both SOD1 mutations heterozygous (5.4%). The haplotype analysis for all BMD revealed no haplotype with both mutated alleles on a single chromosome (Figs S1 and S2). Therefore, these 22 dogs are likely to be compound heterozygous for the SOD1 haplotypes AA and TG."" One of the 22 compound heterozygotes showed clinical signs of degenerative myelopathy. Summarising all available evidence, Pfahler et al. (2014) concluded that ""compound heterozygosity [for the two mutations] may confer a similar risk to DM like the c.118G>A homozygous mutation"".
Ivansson et al. (2016) reported ""that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation""" "By conducting a GWAS on 38 affected and 17 control Pembroke Welsh corgis, each genotyped with the Affymetrix Canine Genome 2.0 Array (yielding 49,663 SNPs for analysis), Awano et al. (2009) highlighted a region of chromosome CFA31 that contains the comparative candidate gene, SOD1.
By conducting a GWAS on 15 affected and 69 control German Shepherd dogs, each genotyped with the Affymetrix v2 canine SNP chip (Yielding 48,415 SNPs for the analysis), Tsai et al. (2012) highlighted a 1.615Mb region on chromosome CFA31 (the same as that highlighted by Awano et al., 2009), which contains the SOD1 gene, mutations in which had already been shown to be causal (see Molecular basis section)." 9615
OMIA:001368 "Tummala et al. (2006) showed the molecular basis of this mutation to be ""a 3-bp deletion (D153del) that . . . deleted a highly conserved aspartic acid residue in the third of seven WD domains in GNB3""." 9031
OMIA:001249 "Utzer et al. (2014): ""A mutation in exon 2 (g.41360196G>A) leads to a premature stop codon at position 190 of the deduced amino acid sequence (p.Trp190ter). Therefore, translation predicts a truncated TYRP1 protein lacking almost completely the tyrosinase domain.""" 9986
OMIA:001130 Li et al. (2006) showed that this disorder is due to a missense variant in the mitochondrial gene for cytochrome b. The variant is a G>A transition as position 14,474 of the mitochondrial genome (NC_002008) predicted to result is a p.V98M substitution on the protein level. This is the first report in domesticated animals of a naturally-occurring base substitution in a mitochondrial gene, leading to an inherited disorder 9615
OMIA:001003 "On the strength of a clear candidate gene in which mutations cause the same disorder in dogs (OMIA 001003-9615), Boudreaux et al. (2007) reported that this disorder in a Simmental calf is due to a missense mutation (c.701T>C) in the CalDAG-GEFI gene which is now called RASGRP2.
Jansen et al. (2013) reported that ""Sanger sequencing confirmed that all thrombopathic animals are homozygous for the [same] pertinent amino acid exchange (c.701T > C, p.L234P, Chr29:43599204"" (UMD3.1 reference coordinates).
Aebi et al. (2016) reported the same causal mutation in affected Simmental cattle in Switzerland." In a GWAS involving 6 affected and 43 normal Fleckvieh (each genotyped with the Illumina BovineHD SNP Chip, yielding 652,856 informative SNPs), Jansen et al. (2013) mapped this disorder in Fleckvieh to chromosome BTA29. Subsequent autozygosity mapping narrowed the region to a 6.3Mb interval that contains the RASGRP2 gene. 9913
OMIA:000421 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Smith et al. (1996) identified the causal mutation as ""a nonsense mutation in the penultimate exon of the [muscle type phosphofructokinase] M-PFK gene [now called PFKM], leading to rapid degradation of a truncated (40 amino acids) and therefore unstable M-PFK protein"". The single base pair mutation (G2228A) is identical in the English springer spaniel, American cocker spaniel and Whippet (Gerber et al., 2009).
Inal Gultekin et al. (2012) reported a different mutation (a point mutation (c.550C>T; p.Arg184Trp) in the same gene as being causative in Wachtelhund dogs." CFA27 9615
OMIA:000081 "Bordbari et al. (2017): ""a 2.7-kb deletion located 4.4 kb downstream of the end of HOXD4 and 8.2 kb upstream of the start of HOXD3. A genotyping assay revealed that both parents of [the affected horse] OAAM1 were heterozygous for the deletion. Additional genotyping identified two of 162 heterozygote Arabians, and the deletion was not present in 371 horses of other breeds""" 9796
OMIA:000852 "Perez et al. (1994) reported that the E allele of the goat alpha(s1)-casein gene, which is associated with reduced casein concentration, contains ""a 457-bp insertion within exon 19 (last untranslated exon). This insert is a truncated long interspersed repeated element (LINE) containing part of the ORF-2, the 3' UTR and the poly(A) tail of the original retroposon.""" 9925
OMIA:001473 "McCormack et al. (2009) reported a missense mutation: ""The sequence of both cDNA clones derived from miniature cattle differed from Bos indicus GH (GenBank AF034386) at base number 641 because there was a cytosine (C) instead of a thymine (T). The C to T change encoded a mutation (threonine to methionine) at amino acid 200 (T200M mutation). The mutation was confirmed by sequencing of an additional 2 miniature cattle and comparing their sequence to 2 normal cattle.""" 9913
OMIA:001612 "Maas et al. (2011) reported that ""the spontaneously occurring chicken ozd mutant contains a large deletion in LMBR1-intron 5, eliminating most of the limb-specific enhancer conserved sequence.""" 9031
OMIA:001984 "Downs et al. (2014) reported that ""a single nucleotide deletion was identified in exon 8 of the TTC8 gene of affected Golden Retrievers. The frame shift mutation was predicted to cause a premature termination codon. In a larger cohort, this mutation, TTC8c.669delA, segregates correctly in 22 out of 29 cases tested (75.9%).""" 9615
OMIA:000161 9913
OMIA:001247 "Thomsen et al. (2010) showed that this disorder is due to a missense mutation (R560Q) at a site that is invariant from insects to mammals in the gene encoding spastin (SPAST or SPG4).
In their table of reduced-fertility haplotypes, Cole et al. (2014) list this SPAST mutation as being the causal mutation for haplotype BHD." Nissen et al. (2001) mapped the locus for this disorder to BTA11. 9913
OMIA:001498 9615
OMIA:001583 Gandolfi et al. (2010) showed that this hypotrichosis mutation (also known as Sphynx hairless) and the Devon rex Curly mutation (OMIA 001581) are both due to mutations in the KRT71 gene which encodes keratin 71. 9685
OMIA:000536 "By cloning and sequencing a very likely candidate gene (based on knowledge that the disorder is due to deficiency of thryroid peroxidase), Fyfe et al. (2003) reported that the causative mutation in Toy Fox Terriers is a C to T transition that creates an early stop codon in the gene coding for thyroid peroxidase (c.331C>T; p. Arg111Ter). Pettigrew et al. (2007) discovered the same causal mutation in Rat Terriers.
Tenterfield Terriers have a C to T missense mutation (c.1777C>T) predicting a tryptophan substitution for a highly conserved arginine residue (p.R593W)(Dodgson et al., 2012).
Fyfe et al. (2013) identified a novel form of TPO mutation in two half-sib Spanish Water Dogs: ""A single guanosine insertion was observed in the first exon of the affected-dog TPO cDNA at a site not previously thought to be within the coding sequence. The insertion allele segregated with the deduced disease allele in the SWD breed and was not observed in unrelated dogs of various breeds. Comparison of the insertion site (an 8-nt poly-G tract) with the orthologous sequences of other mammalian reference genomes revealed that the octa-G tract obliterated the intron 1 splice acceptor site and the exon 2 translation initiation codon found at that position in other species. An in-frame ATG in strong Kozak consensus context was observed in the normal dog sequence 12 codons 5' of the usual mammalian start site, suggesting that dogs have lost the noncoding exon 1 demonstrated in human and mouse. A survey of TPO sequences in other carnivore species indicates that the poly-G tract necessitating an alternative translation initiation site is a canid-specific feature.""
Major et al. (2015) reported a likely causal mutation in the TPO gene in a French Bulldog as a ""T>C transition in the +2 position of the intron 12 splice donor site (CFA17:801,598; TPO c.2242 + 2T>C)""." CFA17 9615
OMIA:001081 "All causative mutations occur within the dystrophin gene, although the molecular basis of the dystrophin mutation may be different between breeds. In the Golden Retriever, there is a point mutation in the consensus splice acceptor site in exon 6 of the dystrophin gene, such that exon 7 is skipped during mRNA processing. The amino acid frame shift causes premature termination of the dystrophin protein (Sharp et al., 1992; Bartlett at al., 1996; Howell et al., 1997).
As reported by Kornegay et al. (2012), a causal ""nonsense mutation in exon 58"" was reported in Rottweilers by Winand et al. (1994).
In two affected German short-haired pointers, Schatzberg et al. (1999) discovered a ""deletion encompassing the entire dystrophin [DMD] gene"". VanBelzen et al. (2017) provided a detailed characterisation of this deletion.
In the Cavalier King Charles Spaniel, Walmsley et al. (2010) reported ""a missense mutation in the 5′ donor splice site of exon 50 that results in deletion of exon 50 in mRNA transcripts and a predicted premature truncation of the translated protein"".
In Corgis, Smith et al. (2011) reported ""a long interspersed repetitive element-1 (LINE-1) insertion in intron 13, which introduced a new exon containing an in-frame stop codon"" as another causal mutation.
As well as reviewing past discoveries, Kornegay et al. (2012) reported that they had ""identified three additional DMD gene mutations in the Cocker spaniel (deletion of four nucleotides in exon 65, with a reading frame shift predicting a premature stop codon at the site of the deletion), Tibetan terrier (a large deletion of exons 8-29), and Labrador retriever (184 nucleotide [pseudoexon] insertion between exon 19 and exon 20, which results in a premature stop codon at the next codon downstream of the insertion) (Larsen CA et al, unpublished). The Labrador retriever mutation presumably corresponds to one in an earlier [abstract] report (Smith et al 2007)"".
Atencia-Fernandez et al. (2015) reported the first causal inversion in a family of Japanese Spitz dogs: ""an inversion of a 5.4-Mb fragment of the X chromosome, with one break point (BP1) in the DMD gene . . . and a second break point (BP2) in a gene farther toward the centromere, the RPGR gene"".
Jenkins and Forman (2015) reported a 1bp deletion in exon 22 (chr CFAX: 27,606,021; CanFam3); c.3084delG; p.Gly1029AspfsX30 [GenBank:NM001003343] in a Norfolk Terrier.
Nghiem et al. (2016) reported ""a 7 base pair deletion in DMD exon 42 (c.6051-6057delTCTCAAT mRNA), predicting a frameshift in gene transcription and truncation of dystrophin protein translation"" as the likely causal variant in a ""dystrophin-deficient Cavalier King Charles Spaniel"".
" CFX 9615
OMIA:000791 The causative mutation of PMDS in the miniature schnauzer is a C to T transition in exon 3 of the Müllerian inhibiting substance type II receptor gene (AMHR2, Wu et al., 2009). 9615
OMIA:001252 9031
OMIA:001763 "Using the sheep SNP50 bead chip to conduct a GWAS for litter size estimated breeding value (EBV) on 378 progeny-tested Norwegian White Sheep rams, Våge et al. (2012) identified a QTL on chromosome OAR5, very near to the GDF9 gene, mutations in which have large effects on fecundity in other breeds of sheep. Subsequent sequencing of this gene in the most extreme sires revealed a SNP ""(c.1111G>A), responsible for a Val->Met substitution at position 371 (V371M). This polymorphism has previously been identified in Belclare and Cambridge sheep, but was not found to be associated with fertility."" The authors concluded that ""Based on the estimated breeding values, daughters of AI rams homozygous for c.1111A will produce minimum 0.46 - 0.57 additional lambs compared to daughters of wild-type rams.""" 9940
OMIA:000327 "By sequencing the most likely of the roughly 20 positional candidate genes (see Mapping section), Tyron et al. (2007) identified a likely causative missense mutation (c.115G>A; p.39G>R) in the gene for cyclophilin B (PPIB).
Ishikawa et al. (2012) confirmed the above mutation as causal, but identified it as c.115G>A; p.6G>R rather than c.115G>A; p.39G>R." By conducting a genome scan on 38 affected and 44 unrelated normal horses, each genotyped with 98 autosomal microsatellites, Tryon et al. (2007) used homozygosity mapping to map this disorder to a 20cM region on chromosome ECA1. Fine-mapping narrowed this region to a 2.5Mb, which (based on deductions from comparative mapping) contains around 20 genes. 9796
OMIA:001661 "Adopting the comparative candidate-gene strategy (based on the similarity of diagnostic signs of a single affected cat with the homologous human disorder), Owens et al. (2012) sequenced the feline CYP11B1 gene (encoding 11β-hydroxylase) in that single affected cat and a healthy control cat, identifying the causal mutation as a G>A missense SNP in exon 7 ""that results in an arginine to glutamine amino acid substitution; this latter mutation results in 11β-hydroxylase deficiency-associated CAH in people"". " 9685
OMIA:001373 "Whole-genome sequencing of one of the affected dogs by Jagannathan et al. (2013), and comparison of this sequence in the ~1.6Mb candidate region with the canine reference sequence revealed four non-synonymous variants, one of which ""turned out to represent an artifact due to an error in the reference genome assembly"". Genotyping of the other three variants in a large (>500) cohort of affected and control dogs identifed the causal mutation as c.972T>G in the SUV39H2 gene ""encoding the “suppressor of variegation 3-9 homolog 2 (Drosophila)”, a histone 3 lysine 9 (H3K9) methyltransferase"". ""The variant results in the change of an asparagine residue in the catalytically active SET domain to a lysine (p.N324K). The SET domain has been named according to the first proteins, in which it has been identified, Suvar(3)9, enhancer of zeste, and trithorax. SIFT and Polyphen-2 predict that the p.N324K variant affects protein function . . . . The asparagine at position 324 is highly conserved across all known SUV39H2 orthologs and even across many other related H3K9 methyltransferases"". The same authors also comment that ""A loss of SUV39H2 function is predicted to result in delayed differentiation, which is compatible with the histopathological changes that we observed in biopsies from nasal epidermis of HNPK affected Labrador Retrievers.""" "A GWAS conducted by Jagannathan et al. (2013) on 13 affected and 23 control Labrador retrievers, each genotyped with the Illumina canine HD chip (yielding 106,681 informative SNPs), mapped this disorder to an approximately 4Mb region on chromosome CFA2. Subsequest homozygosity mapping narrowed the candidate region to approximately 1.6Mb ""from 20,818,258–22,414,948 bp (CanFam 3.1 assembly)"" which contains 15 annotated genes." 9615
OMIA:001327 "By conducting a GWAS with the 173k illumina canine HD chip in each of two breeds (Kromfohrländer: 13 cases and 29 controls, with 77,903 informative SNPs; Irish Terrier: 10 cases and 21 controls, with 82,671 informative SNPs), Drögemüller et al. (2014) mapped this disorder to a single region on chromosome CFA5. Homozygosity mapping across the two breeds narrowed the candidate region to 611kb (CFA5: 40,521,040–41,131,739 CanFam 3.1 assembly), containing 13 genes. Comparison of the relevant sequence from whole-genome sequencing of an affected Kromfohrländer at 23.5x coverage, with relevant sequence from 46 non-affected dogs from other breeds identified the causal mutation as ""a missense variant (c.155G>C) in the FAM83G gene encoding a protein with largely unknown function. It is predicted to change an evolutionary conserved arginine into a proline residue (p.R52P)"". The causality of this variant was confirmed by genotyping of this mutation in other affected and normal dogs.
In a proof-of-concept project to detect a likely causal mutation without GWAS, Sayyab et al. (2016) reported the first use of whole-genome sequencing of a family trio (affected offspring and its two non-affected parents) which enabled them to confirm the causal mutation reported by Drögemüller et al. (2014): ""527 single nucleotide variants (SNVs) and 15 indels were found to be homozygous in the affected offspring and heterozygous in the parents. Using the computer software packages ANNOVAR and SIFT to functionally annotate coding sequence differences and to predict their functional effect, resulted in seven candidate variants located in six different genes. Of these, only FAM83G:c155G>C (p.R52P) was found to be concordant in eight additional cases and 16 healthy Kromfohrl änder dogs.""" 9615
OMIA:001371 "Using a candidate gene strategy (based on the homologous disorder in humans), Penderis et al. (2007) sequenced ""all 10 canine L2HGDH exons (with flanking intron regions) from the [Staffordshire bull terrier] affected dogs and two carrier dogs"" and identified a causal mutation as ""two single‐nucleotide substitutions separated by a single invariant T nucleotide in exon 10 (c[1297T→C; 1299c→t]; p[Leu433Pro; His434Tyr])"". Sanchez-Masian et al. (2012) identified a different mutation in the same gene in a family of Yorkshire Terriers: a base substitution ""at the translation initiation codon of the homolog canine L2HGDH gene was detected (c.1A>G; p.Met1?)"". Farias et al. (2012) reported the same mutation in the same breed." 9615
OMIA:001228 By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Inaba et al. (1996) showed in a population of Japanese Black cattle, that this disorder is due to a nonsense mutation (CGA>TGA; Arg>Stop) in the gene for band 3 of red cell membrane, at the position corresponding to codon 646 of the human gene. The lack of this protein produces very unstable red-cell membranes, resulting in anaemia and retarded growth. 9913
OMIA:000844 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Giger et al. (1997) identified a causative mutation as a splicing defect in the R/L-PK gene that gives rise to 13-bp deletion (Barrs et al., 2009). The gene symbol is now PKLR. Grahn et al. (2012) reported that the splicing defect and hence deletion is a consequence of a ""a guanine to adenine transition in intron 5, 304 bp 3' of the exon 5 splice-donor site and 53 bp upstream from the exon 6 splice-acceptor site [""c.693+304G>A""]. The mechanism by which this mutation results in the erroneous splicing of exons 5 and 6 has yet to be determined.""" 9685
OMIA:001826 "For eight of the nine haplotypes with a significant effect on calving rate (see Mapping section), Fritz et al. (2013) searched for causal mutations via whole-genome sequence data from 25 Holstein, 11 Montbéliarde and nine Normande bulls which had made major contributions to their breed. Specifically, they filtered ""for mutations that were (a) located at+or –6 Mb from the detected haplotype (b) carried in the heterozygous state by the carrier bulls and (c) absent from the non carrier bulls from the three breeds"" and then examined identified polymorphisms for their likely effect on protein structure and function. For HH4, Fritz et al. (2013) provided convincing evidence for a candidate causal mutation, namely a missense mutation (g.1277227A.C; UMD 3.1 genome assembly) in the GART gene (which encodes glycinamide ribonucleotide transformylase), leading to p.N290T. " "By analysing Illumina Bovine 50k Beadchip genotype data from 47,878 Holstein, 16,833 Montbéliarde and 11,466 Normande cattle in the French genomic selection database, Fritz et al. (2013) identified 34 common (>1%) haplotypes that have a significant deficit (P<10^-4) of homozygotes in live animals, and which are, therefore, each likely to harbour a deleterious mutation. Three of these haplotypes, namely BY (Brachyspina; OMIA 000151-9913), HH1 (OMIA 000001-9913) and HH3 (OMIA 001824-9913), had been reported by VanRaden et al. (2011; J Dairy Sci 94:6153-61). Following the convention of naming such haplotypes with a first letter indicating breed, a second letter H for haplotype, followed by a sequential number, Fritz et al. (2013) named their 14 new Holstein haplotypes as HH4 to HH17, their 11 Montbéliarde haplotypes as MH1 to MH11, and their six Normande haplotypes as NH1 to NH6. Analyses of reproductive data indicated that nine of the 34 haplotypes have a significant effect on fertility, including six of the newly identified haplotypes, namely HH4, HH5, HH6, MH1, MH2 and NH5.
This present OMIA entry is for HH4, which is located in chromosome BTA1, at 1.9-3.3Mb (UMD 3.1 genome assembly) (Fritz et al., 2013)." 9913
OMIA:001961 The FecG(V) allele is a missense mutation: c.943C>T; p.Arg315Cys in the cleavage site of the propeptide encoded by GDF9 (Souza et al., 2014) 9940
OMIA:001431 "LeVine et al. (2009) reported ""A unique single base deletion (guanine) was identified at the exon 4-intron junction . . . in the affected dog's genomic DNA""" 9615
OMIA:000394 "As reported by Ng et al. (2012): ""Sequence analyses of the keratin gene cluster identified a 69 bp in-frame deletion in a conserved region of KRT75, an α-keratin gene. Retroviral-mediated expression of the mutated F cDNA in the wild-type rectrix qualitatively changed the bending of the rachis with some features of frizzle feathers including irregular kinks, severe bending near their distal ends, and substantially higher variations among samples in comparison to normal feathers. These results confirmed KRT75 as the F gene."" " Using a genome-wide scan of 45 birds in 5 families with 2678 SNPs, Ng et al. (2012) linkage-mapped the Frizzle locus to the linkage group E22C19W28_E50C23 on chromosome E22. From the chicken genome assembly, it was evident that this region contains a cluster of keratin genes. 9031
OMIA:001688 "Hauswirth et al. (2012) reported three independent mutations causing the splashed white phenotype, two of them in the MITF gene and one in the PAX3 gene: A missense mutation in the PAX3 gene (c.209G>A; p.C70Y; ""SW2""), which arose in the year 1987 in a Quarter Horse mare. It has only been encountered in Quarter Horses and American Paint Horses, which descend from this founder mare.
Hauswirth et al. (2013) reported a second missense variant in the PAX3 gene in an Appaloosa family segregating for a splashed white phenotype (c.95C>G; p:Pro32Arg).
Table S1 of Dürig et al. (2017) provides details of all PAX3 alleles (plus alleles at EDNRB, KIT, MITF) known in July 2016. " 9796
OMIA:001709 "Masuyama et al. (2012) reported a mutation in the DMRT1 gene that results in chromosomally XY (male) medaka fish developing ""into normal females and [laying] eggs"". They further reported that ""The mutant phenotype could be rescued by transgenesis of the Dmrt1 genomic region.""" 8090
OMIA:001319 From a BAC contig encompassing the candidate region of the bovine MHC (see Mapping section above), Sugimoto at al. (2003) determined that this disorder in Holstein-Friesian cattle is due to the deletion of one of two HSP70 (heat-shock protein) genes in the bovine major histocompatibility complex. A genome scan with 1200 microsatellites enabled Sugimoto et al. (2003) to linkage map the HMDM locus to the bovine MHC on chromosome BTA23q21. 9913
OMIA:001199 Schneider et al. (2015): likely causative mutation in MC1R is C125R 46844
OMIA:000240 "Vickrey et al. (2015) ""identified a G to A mutation in the sixth exon of EphB2 of crested birds (cr dove); this change is predicted to result in a glycine to arginine amino acid substitution at position 636 of the protein (Gly636Arg)"" " 328808
OMIA:001554 The causative mutations for Cmr3 in the Lapponian herder are a deletion and a G to T substitution in exon 10 of BEST1 (Zangerl et al., 2010). CFA18 9615
OMIA:000006 "By comparing the whole-genome sequence of 6 pairs of full-sibs from the Chinese Xingyi bantam breed, each pair comprising the same contrasting Cp genotypes (Cp/+ vs +/+), Jin et al. (2016) identified ""a 11,896 bp large deletion region (chr7: 21,798,705-21,810,600) covering the entire Indian hedgehog (IHH) gene"" as the likely causal mutation. Subsequent PCR genotyping for the deletion in ""511 samples (embryos, n = 130; chickens, n = 381)"" from Cp/+ x Cp/+ matings showed a complete association between genotype and Creeper phenotype. The authors note that ""As one of the key genes driving animal body development, IHH is conserved in gene function and signaling pathway in the major animal clades and is required for embryonic bone formation in development""." 9031
OMIA:000441 "By sequencing the most likely functional positional candidate gene from the mapped region (see Mapping section), Littlejohn et al. (2014) identified a causal mutation as a ""nonsynonymous SNP in exon 5 [that] encodes a p.Cys221Gly substitution highly conserved across vertebrates and other structurally related hormones, disrupting one of three disulphide bonds defining the three-dimensional (3D) structure of mature prolactin hormone"" (ss1067289409; chr23:35105313A>C)" "By ""genome-wide transmission disequilibrium testing using 628,278 single-nucleotide polymorphisms (SNPs) in 22 nuclear trios and 55 half-sib offspring of the two founder sires"", Littlejohn et al. (2014) mapped this syndrome to a region on chromosome BTA23." 9913
OMIA:000710 "By sequencing the most obvious candidate gene, Davidson et al. (2007) identified a causal mutation as ""a single nucleotide substitution at base 115 as the cause of ARHN in English Cocker Spaniels. This mutation, which causes a premature stop codon in exon 3 of COL4A4 was segregated with clinical status in all affected dogs and obligate carriers"".
Nowend et al. (2012) reported a different mutation in the same gene in English Springer Spaniels: ""a single nucleotide substitution in COL4A4 at base 2806 resulting in a premature stop codon""." 9615
OMIA:001577 The causative mutation is an adenosine deletion causing premature termination of AGL translation (Gregory et al., 2007). There is an analogous human condition (OMIM# 232400). CFA6 9615
OMIA:001715 "From a genome scan of 70 Icelandic horses (40 that can pace and 30 that can't pace), Andersson et al. (2012) identified a 684kb region of chromosome ECA23 showing a very strong association with ability to pace. Resequencing within this region eventually identified the causative mutation as a nonsense mutation (Ser301STOP) in DMRT3 (currently listed as LOC100147177 in NCBI), which encodes a transcription factor with a DM domain. Detailed analysis of wild-type and DMRT3-null mice revealed that Dmrt3 has ""a pivotal role for configuring the spinal circuits controlling stride in vertebrates"". In horses, ""The [DMRT3] mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance"". In Icelandic horses, ""homozygosity for the DMRT3 nonsense mutation is required for the ability to pace in this breed"". " 9796
OMIA:000782 In a striking piece of detective work, Wright et al. (2009) showed that the gene for pea-comb is SOX5, an important transcription factor. The wild-type allele at this locus (which results in normal combs and wattles) has a duplication of approximately 2.5kb of sequence near an evolutionarily conserved region in intron 1. The pea comb mutant phenotype results from large-scale amplification of this duplication: pea comb alleles typically have 20-40 copies of the duplicated sequence, which must be sufficient to interfere with transcription. Thus the pea comb mutation is a regulatory mutation. "The first evidence of linkage involving the pea-comb locus was obtained by Hertweg (1933), who showed pea comb is linked to ""marbling"" down pattern. Bruckner and Hutt (1939) extended this linkage group to include blue egg. Warren (1949) provided additional data for this linkage group. Several decades later, this linkage group was shown by Bitgood et al. (1980) to correspond to chromosome GGA1. Using a set of SNPs chosen specifically for this purpose, Wright et al. (2009) fine-mapped the locus to the region 67,831,796-68,456,921 bp of GGA1, which contains just one gene, namely SOX5." 9031
OMIA:000578 9544
OMIA:001450 """A missense mutation (C1676T) leading to a R559C substitution in exon 14 of ATP2A1"" (Charlier et al., 2008)" "In a pioneering use of tens of thousands of SNP markers (""using either the 25K Affymetrix SNP panel or a custom-made 60K Illumina panel""), Charlier et al. (2008) identified a single 2.12 Mb region on BTA25 in which 12 affected calves were significantly more homozygous for the same allele at each of many SNPs, when compared with 14 normal controls. An investigation of comparative candidate genes in this region identified six possible candidate genes. Sequencing revealed the causative molecular lesion in the ATPA2A1 gene, whose peptide is involved in calcium flow into the sarcoplasmic reticulum." 9913
OMIA:001967 "Steffen et al. (2015) sequenced the complete genome of an affected Landseer at 14.2x coverage. The dog had ~2.8 million homozygous variants compared to the Boxer reference genome. When concentrating on the critical intervals and comparing the data to 170 dog genomes from control dogs of other breeds, only one private non-synonymous variant remained in the affected Landseer, a nonsense variant in the COL6A1 gene on chromosome 31, c.289C>T or p.Glu97*. This variant perfectly co-segregated with the phenotype in cohort of 58 Landseer dogs including 5 affected dogs.
Collagen VI is made up of three different subunits encoded by the COL6A1, COL6A2, and COL6A3 genes. Variants abolishing the function of either these genes lead to a severe muscular dystrophy phenotype in humans, the so-called Ullrich congenital muscular dystrophy. Based on the knowledge from humans, the identified canine COL6A1 nonsense variant seemed a very likely candidate causative variant for the Landseer disease. Steffen et al. (2015) genotyped 404 Newfoundland dogs and 473 dogs from diverse other breeds and did not find the mutant allele in these breeds." Steffen et al. (2015) used one complete Landseer family with 3 affected and 3 non-affected offspring and one additional distantly related affected Landseer to map the disease causing variant. Using a combination of linkage and homozygosity mapping they narrowed the most likely postions for the causative variant to two genome segments on chromosome 10 and 31 comprising a total of 4.8 Mb. The specific critical intervals were defined as Chr10:61,871,450 - 66,047,210 and Chr31:38,752,158 - 39,364,930 (CanFam 3 assembly). 9615
OMIA:001590 "By cloning and sequencing a very likely candidate gene (based on knowledge that the mask phenotype is due to an allele at the Extension locus, which is known to be encoded by the MC1R gene), Schmutz et al. (2003) reported that ""All dogs with a melanistic mask had at least one copy of a valine substitution for methionine at amino acid 264 (M264V)"", resulting from ""an A to G transition in the first position of codon 264"" in the canine MC1R gene." 9615
OMIA:002029 "Michot et al. (2016): ""a one base pair insertion (Chr14: g.23995411_23995412insA) that affects the retinitis pigmentosa-1 gene (RP1) . . . [and] is predicted to cause a frameshift at codon 791 and to terminate the protein 13 amino acids later (p. R791KfsX13)""." 9913
OMIA:001401 A T>A base substitution in intron 6 of MITF leads to the skipping of exon 7 and a premature termination. 10036
OMIA:001071 "Fieten et al. (2016): ""The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation . . . We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis""" 9615
OMIA:001588 "The Golden Retriever causal mutation was reported by Grall et al. (2012) to be an ""insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs"". Using the genetic variant nomeclature as of 2015, the causative variant can be described as c.1445_1447delinsTACTACTA or p.N482Ifs*11." Unlike ichthyosis in the Jack Russell terrier (OMIA 000546-9615) which maps to canine chromosome CFA8 (TGM1 gene), and ichthyosis in the Norfolk terrier (OMIA 001415-9615) which maps to canine chromosome CFA9 (KRT10 gene), ichthyosis in Golden Retrievers maps to a locus on CFA12 (PNPLA1 gene), as shown by Grall et al. (2012), who conducted a GWAS on 20 affecteds and 20 controls, each genotyped with the Affymetrix v2 canine SNP. 9615
OMIA:000831 "Based on a comparative positional cloning approach (the canine disorder maps to a location on the canine X chromosome that is homologous with the location of the same disorder (RP3) in humans, which is due to mutations in the RPGR gene), Zhang et al. (2002) identified a ""five-nucleotide deletion (delGAGAA) between 1028 and 1032"" in the canine RPGR gene as a causal mutation for a form of X-linked PRA they call XPRA1. The authors also noted that ""The XLPRA1 mutation causes a frameshift and immediate premature stop; the truncated protein is missing 230 C-terminal amino acids, causing a slight decrease in the isoelectric point (3.89 versus 4.01 in normal). By mutation scanning, we also found the same five-nucleotide deletion in the Samoyed breed with a clinically similar X-linked retinal degeneration (data not shown)""
Kropatsch et al. (2016): ""Whole exome sequencing in two PRA-affected Weimaraner dogs identified a large deletion [maximum size 5,006 bp] comprising the first four exons of the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene""." 9615
OMIA:002033 Gallinet et al. (2013): c.245A>C; p.H82P (with respect to accession no. M55158; was previously p.H67P) 9913
OMIA:000588 "By sequencing the positional candidate gene ADAMTS17, Farias et al. (2010) identified the causal mutation as ""a G→A transition at c.1473+1, which destroys the splice donor recognition site in intron 10""." "Sargan et al. (2007) conducted a genome scan with 364 microsatellites on ""23 PLL-affected miniature bull terriers, together with an equal number of obligate PLL carriers with no luxation, and also 23 PLL-affected Lancashire heeler, with an equal number of obligate carriers with no luxation"". A linkage analysis highlighted ""a 6.3-Mbp region in the central part of chromosome 3"".
By conducting a GWAS on 28 affected and 20 control Jack Russell Terriers, each genotyped with the CanineSNP20 BeadChip, Farias et al. (2010) highlighted the same region on chromosome CFA3 as identified by Sargan et al. (2008). Subsequent fine-mapping narrowed the region to a 664kb segment harbouring the positional candidate gene ADAMTS17." 9615
OMIA:001695 "Kondo et al. (2001) provided strong evidence suggesting that the recessive allele is a mutant of the EDAR gene that contains ""several kb of extra sequence in the 5′ UTR that . . . contains out-of-frame start codons and stop codons, [and consequently] the mutant transcript is likely to result in premature initiation and termination of translation and, as a result, the EDAR protein is not synthesized""" Kondo et al. (2001) mapped this trait to medaka linkage group LG21, and then used knowledge of conserved synteny with zebrafish and humans to identify 14 potential positional candidate genes, 10 of which mapped to LG21. Of these 10, the EDAR gene showed zero recombination with the trait. 8090
OMIA:000272 The 750kb candidate region on CFA18 identified by Karlsson et al. (2007) (see Mapping section) contains five genes, three of which are fibroblast growth factor (FGF) genes that in chickens have an integral role in embryonic development. In an accompanying paper in the same issue of Nature Genetics, Salmon Hillbertz et al. (2007) reported that the hair-ridge phenotype (which predisposes to dermoid sinus) is due to a large duplication encompassing all three FGF genes (FGF3, FGF4, FGF19) and another gene ORAOV1. "In a landmark study, Karlsson et al. (2007) mapped the hair-ridge locus to a 750kb region on chromosome CFA18 via one of the first Genome-Wide Association Studies (GWAS) using 27,000 SNPs on just ""9 ridgeless Rhodesian ridgebacks and 12 ridged controls"". " 9615
OMIA:002028 "Gentilini et al. (2016): ""a homozygous c.1987C>T (Ensembl transcript ID: ENSCAFT00000027699) or c.1753C>T (Ensembl transcript ID: ENSCAFT00000049922) [nonsense] substitution, which results in a premature termination codon (p.663Arg*) in the superoxide domain"" of the gene encoding myeloperoxidase (MPO)." 9615
OMIA:001299 "The tva gene (i.e. the gene encoding the receptor for subgroup A viruses) was isolated, cloned and partially sequenced by Young et al. (1993), who performed two rounds of transfection with chicken genomic DNA (first into a monkey cell line and then into a mouse cell line) and subsequent selection for clones that are susceptible to subgroup A virus (and hence must be expressing the receptor for subgroup A viruses).
Elleder et al. (2004) fully sequenced this gene, and reported that two ""different defects were identified in cDNAs cloned from two different ASLV(A)-resistant inbred chickens, line C and line 7(2). Line C tva(r) contains a single base pair substitution, resulting in a cysteine-to-tryptophan change in the LDLR-like region of Tva. This mutation [called allele tva^1] drastically reduces the binding affinity of Tva(R) for the ASLV(A) envelope glycoproteins. Line 7(2) tva(r2) contains a 4-bp insertion in exon 1 that causes a change in the reading frame, which blocks expression of the Tva receptor."" This allele is called tva^r2.
Reinišová et al. (2012) identified two more resistance alleles at this locus, both disrupting splicing: tva^r3 is a 10bp deletion in intron 1 that includes a critical nucleotide of the deduced branch-point signal; tva^r4 is a 5bp deletion which also destroys the branch point signal.
Chen et al. (2015) identified two more resistance alleles, namely tva^r5 (""a [10bp] deletion of the sequence CGCTCACCCC (nucleotides 502 to 511)"") and tva^r6 (""a [15bp] deletion of the sequence CGCTCACCCCGCCCC (nucleotides 502 to 516)"")." Bates et al. (1998) reported that the tva gene maps to within 5 cM of the receptor gene identified by Young et al. (1993), which (given the limited power of the linkage analysis) was strong evidence that the two genes are one in the same. 9031
OMIA:001340 Careful examination of the potential effects of mutations in any of the roughly 20 comparative candidate genes (see Mapping section), followed by mapping and sequencing of the most likely candidate gene, led Thomsen et al. (2006) to discover that CVM is caused by a missense mutation (c.559G>T) leading to V180F in the SLC35A3 gene, which encodes solute carrier family 35, member A3. Subsequent genotyping of this mutation in large numbers of other cattle confirmed that it is causal. (Mohammad Shariflou 11/11/2006; FN 12 June 2013). "By conducting a genome scan on 7 affected calves and their normal parents, each genotyped for 194 microsatellites, Thomsen et al. (2006) homozygosity-mapped this disorder to around 60cM on chromosome BTA3. Subsequent fine-mapping followed by comparative mapping of BACs containing the most likely candidate markers narrowed the candidate region of around 5.6Mb corresponding to human chromosome HSA1p21.2-21.3, which contains around 20 known or predicted genes.
In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) confirmed the mapping of this disorder to BTA3 at 40-46Mb (UMD 3.0 genome assembly)." 9913
OMIA:001944 "Comparative analysis by Willet et al. (2015), based on location and phenotype in the mouse, revealed 19 positional comparative candidate genes. Whole-genome sequencing of two of the affected sibs revealed 5 candidate functional mutations, which were subsequently narrowed down to the causal mutation, a ""guanine deletion at CFA5:35,940,090 (CFA5:32,945,846 in canFam3.1) within exon 2 of HES7 (c.126delG) . . . [which] introduces a frameshift mutation, causing alteration from the 43rd amino acid onwards and resulting in a premature termination codon in place of the 66th amino acid (p.(Thr43ProfsTer24))"". Genotyping for this mutation in 133 dogs, including the three affected dogs and extended family members, confirmed this as the causal mutation." By conducting a GWAS on a family comprising normal parents plus 3 affected and 5 normal offspring, each genotyped with the Canine HD BeadChip (yielding 73,921 informative SNPs), Willet et al. (2015) mapped this disorder to a 25 Mb region on chromosome CFA5:29.84Mb–45.26Mb. 9615
OMIA:001341 "RNA sequencing ""from five samples (three from skin and two from retina)"" enabled Bellone et al. (2011) to identify the causal mutation as a retroviral long terminal repeat (LTR) insertion in TRPM1. Details were provided by Bellone et al. (2013): the causal mutation is ""a 1378 bp insertion in intron 1 of TRPM1""." "A genome scan on 27 half-sibs segregating this trait, each genotyped with 102 microsatellites, enabled Terry et al. (2004) to linkage-map this trait to chromosome ECA1. Linkage analyses with additional markers on additional horses in the candidate region enabled Terry et al. (2004) to refine the location to a region of approximately 6cM ""between microsatellite markers ASB08 and 1CA43"". Comparative mapping analysis enabled Terry et al. (2004) to suggest TRPM1 (encoding transient receptor potential cation channel, subfamily M, member 1) as a potential comparative positional candidate gene. By judicial sequencing and SNP genotyping, Bellone et al. (2010) narrowed the candidate region to ""A single 173 kb haplotype associated with LP and CSNB (ECA1: 108,197,355- 108,370,150)"" which contains TRPM1.
From segregation analysis, Holl et al. (2016) concluded there is a major gene that modifies the extent of white in Leopard complex spotting. They mapped this gene, which they named PATN1 (for pattern-1), to a 15Mb region on chromosome ECA3p." 9796
OMIA:001596 "By sequencing the most likely of 9 positional candidate genes (see Mapping section), Seppälä et al. (2011), part of the LUPA consortium, discovered that this type of epilepsy in the Lagotto romagnolo breed is due to a nonsense mutation (c.1552A>T (p.K518X)) in the gene for LGI2. Noting that mutations in this gene have not yet been reported to be causative of epilepsy in humans, but that mutations in a ""sister"" gene, LGI1, result in lateral temporal lobe epilepsy in humans, the authors go to considerable lengths to describe how this discovery in dogs may well inform future studies of the genetic basis of epilepsy in humans. " By conducting a GWAS on 11 discordant sib-pairs (7 full-sibs and 4 half-sibs) of the Lagotto romagnolo breed, each genotyped with the Affymetrix's Canine SNP Array version 1 (yielding 17,273 informative SNPs for analysis), Seppälä et al. (2011) mapped this disorder to a region on chromosome CFA3. Subsequent homozygosity mapping narrowed the region to 1.7Mb between 87.3 and 89.0Mb, which contains 9 genes. 9615
OMIA:001901 "As reported by Kadri et al. (2014), one of the genes in the deletion (see Mapping section), namely RNASEH2B, is ""known to cause embryonic lethality when knocked-out in the mouse"". Subsequent investigations confirmed that this deletion is a recessive embryonic lethal in cattle but ""is associated with a positive effect on milk yield and composition"", which results in selection favouring heterozygotes (balancing selection), thereby maintaining the lethal deletion in the population." "By conducting a GWAS on 4,072 Holstein-Friesian, 1,177 Jersey, 894 Danish Red, 1,714 Swedish Red, and 2,242 Finnish Ayrshire progeny-tested bulls, each genotyped with the 50K bovine SNP chip (yielding 37,123 informative SNPs across the five breeds), Kadri et al. (2014) identified a QTL for fertility on chromosome BTA12 in Finnish Ayrshires and Swedish Reds. By utilising additional genotyping and whole-genome next-gen sequencing data, these authors were able to attribute the QTL to a 662,463 bp deletion between 20,100,649 to 20,763,116 bp, which ""encompasses three protein-encoding genes (RNASEH2B, GUCY1B2 and 3 out of 4 exons of FAM124A), one gene with uncertain coding potential (DLEU7) and two non-coding RNA genes (DLEU7-AS1 and LINC00371)""." 9913
OMIA:002092 "In the first published success of genome-wide RNA sequencing (mRNA-seq) in domestic animals, Forman et al. (2012) sequenced the mRNA from the cerebellum of one affected dog. The canine sequence data were compared with sequence of 27 human genes in which mutations have caused similar clinical signs in humans, and which have canine homologues. One of the canine homologues, SPTBN2, turned out to have an 8bp deletion which segregates perfectly with the canine disease. The deletion is in exon 29 ""is predicted to result in a run of 27 aberrant amino acids, followed by premature termination with a 410 amino acid truncation p.G1952insRDRGQGRPLLLMHRHGAGAACQEPLCS*"" " 9615
OMIA:001089 9590
OMIA:001426 "In uncovering a previously-unrecognised source of variation, Clop et al. (2006) reported : ""We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation."" GDF8 is now known as MSTN (myostatin), and the mutation is g+6223G>A; c.*1232G>A.
Hu et al. (2013) showed that ""Knockdown of myostatin expression by RNAi enhances muscle growth in transgenic sheep"".
Haynes et al. (2013) reported that ""lambs homozygous for the MSTN g+6723G>A mutation have changes in carcass characteristics (dressing and total lean), organ weights, and muscle fiber number. This may be due to reduced myostatin protein early in utero, but after 4 wk of age there was no difference in the abundance of mature myostatin protein in muscle or plasma among MSTN A/A, MSTN A/G, and MSTN G/G genotypes.""" 9940
OMIA:000155 "The first report of the molecular basis of this disorder was by Ameratunga et al. (1998) who, by cloning and sequencing a very likely comparative candidate gene (based on the homologous human and mouse disorders) in a colony of Brittany dogs segregating for C3 deficiency, identified a frameshift due to ""a deletion of a cytosine at position 2136 (codon 712), leading to a frameshift that generates a stop codon 11 amino acids downstream""." 9615
OMIA:001520 "Fine mapping and subsequent sequencing enabled Kropatsch et al. (2010) to identify the causal mutation as ""a deletion of exons 15 and 16 which alters the reading frame leading to a premature stop codon"" in the ADAM9 gene.
A week later came a report of an independent exhaustive evaluation of candidate genes (both comparative positional and positional) that eventually enabled Goldstein et al. (2010) to identify the same causal mutation, namely ""a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein""." "By conducting an autozygosity-mapping analysis on 12 affected and 12 matched control Glen of Imaal Terriers, each genotyped with the Affymetrix Canine Genome 2.0 Array “Platinum Panel” (comprising ""∼50.000 SNPs""), Kropatsch et al. (2010) highlighted a region on ""CFA16 from 24.7 to 29.9 Mb"".
In an independent study published just a week after Kropatsch et al. (2010) Goldstein et al (2010) undertook a GWAS on 21 affected and 22 matched control Glen of Imaal Terriers, each genotyped with the Affymetrix Version 2 Canine SNP chip (yielding 60,245 informative SNPs for analysis), Goldstein et al. (2010), highlighting a region on chromosome CFA16 ""shared by six SNPs comprising an interval of approximately 4.4 Mb"". " 9615
OMIA:000370 "Gunnarsson et al. (2007) showed that the cinnamon allele (AL*C) corresponds to a missense mutation: c.287C>A; p.Ala72Asp in theSLC45A2 gene.
Gunnarsson et al. (2007) showed that the sex-linked albino allele (AL*A) corresponds to a splice-site mutation in the SLC45A2 gene: ""a G → T transversion at the splice acceptor site just preceding exon 4""." 93934
OMIA:001413 This entry records the artificial creation of a mutant retinitis pigmentosa line of pigs by Ross et al. (2012) by somatic cell nuclear transfer (SCNT) of a mutated form (Pro23His) of the human RHO gene into a line of miniature pigs. 9825
OMIA:001982 "In a patent application, Winand (2011) documented a likely causal mutation as c.2032G>A, p.Gly678Arg in the PLOD1 gene encoding procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1.
" 9796
OMIA:001683 "By sequencing their candidate region (see Mapping section) in affected and normal dogs, Forman et al. (2012) eventually revealed the causative mutation as a ""single base deletion in exon 5"" in a gene with the somewhat unusual name of Family with sequence similarity 83, member H (FAM83H). Using the genetic variant nomenclature as of 2015, the cuastaive variant can be descripted as c.977delC or p.Pro326Hisfs*258." By conducting a GWAS on 23 affected and 38 control Cavalier King Charles Spaniels, each genotyped with the Illumina Canine HD SNP chip (yielding 91,427 SNPs for analysis), Forman et al. (2012) highlighted a region on chromosome CFA13. 9615
OMIA:001335 The causal mutation was discovered via a comparative positional cloning approach. Building on the mapping results described in the Mapping section above, Lingaas et al. (2003) narrowed the candidate region homologous to human HSA17p, which includes the BHD gene, mutations in which cause Birt–Hogg–Dubé syndrome, which is very similar to the canine disorder. Sequencing of the canine BHD gene showed that this disorder in German Shepherd dogs is due to an A>G base substitution in exon 7 of the BHD (folliculin) gene, leading to a H255R amino-acid substitution in a highly conserved region. Using genetic variant nomenclature as of 2015, the causative variant would be denoted as c.764A>G or p.His255Arg. "Using a genome scan with mapped microsatellites, Jónasdóttir et al. (2000) mapped the RCND locus to ""a small region of canine chromosome 5. The closest marker, C02608, is linked to RCND with a recombination fraction (θ) of 0.016, supported by a logarithm of odds score of 16.7"". To the authors' knowledge, this was ""the first localization of a mammalian cancer syndrome to be mapped in a species other than human and rat""." 9615
OMIA:000640 "Fieten et al. (2016): "" the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation""" Guevara-Fujita et al (1996) mapped the canine Menkes gene to the X chromosome. 9615
OMIA:001988 "van der Sluis et al. (2002) refined ""the localization of the copper toxicosis gene to a region of <500 kb [in CFA10q26] by linkage disequilibrium mapping. While screening genes and expressed sequence tags in this region for mutations we found that exon 2 of the MURR1 gene is deleted in both alleles of all affected Bedlington terriers and in single alleles in obligate carriers."" Detailed study of this deletion enabled Forman et al. (2005) to report that the deletion ""breakpoints were positioned at 65.3091 and 65.3489 Mb of dog chromosome 10, in intron 1 and intron 2 of COMMD1 respectively, a deletion of 39.7 kb. The two breakpoints share sequence homology suggesting that homologous recombination may have been responsible for the deletion"". " "Yuzbasiyan-Gurkan et al. (1997) performed a genome scan with 213 microsatellites on Bedlington Terrier families comprising 77 animals, 25 of which were affected. One closely linked (0 cM) microsatellite (C04107) was identified. van der Sluis et al. (1999) FISH-mapped a BAC clone containing this microsatellite to a metaphase spread of canine chromosomes, showing that the marker, and hence the disorder gene, is on canine chromosome CFA10q26, in a region of conserved synteny with human chromosome HSA2p13–p16. Detailed analysis of this BAC revealed sequence highly similar to that of an exon of the MURR1 gene of humans and mouse. Radiation-hybrid mapping of this gene revealed it to be located in HSA2p13–p16, i.e. the region showing conserved synteny with the region of CFA10 that includes the canine disorder gene.
Haywood et al. (2016) reported that the causal gene for non-COMMD1 Bedligton Terriers with this disorder maps to chromosome 30 in a region that ""contains the ABCA12 gene which bears a close functional relationship to ATP-ase 7B responsible for Wilson's disease in man."" Thus, most of the references and text in this OMIA entry actually apply to an ""atypical"" form of Wilson disease." 9615
OMIA:002083 "A genome-wide CNV (copy number variation) association study of 791 Japanese Black cattle enabled Sasaki et al. (2016) to identify a ""34-kb deleted-type"" CNV region, identified as CNVR_322, ""associated with embryonic mortality at 30-60 days after artificial insemination. The CNV harbors exon 2 to 6 of ANNEXIN A10 (ANXA10). . . . Western blot analysis showed that the CNV results in a null allele of ANXA10."" " 9913
OMIA:002109 "Hofstetter et al. (2017): ""Genome-wide filtering for sequence variants in the whole genome that were present heterozygous only in the affected calf and homozygous wild-type (WT) in the genomes of both parents, resulted in 276 variants representing putative de novo sequence variants (Table S1). Out of these 276 variants, only a single 10 bp insertion on chromosome 19 (g.37298375_37298376insGGAGCACAGG) was located in a protein coding gene, namely in exon 3 of the bovine distal-less homeobox gene (DLX3) leading to a frameshift. . . . The mutation was predicted to produce a frameshift downstream the homeobox encoding region of the DLX3 mRNA (NM_001081622: c.584_585insGGAGCACAGG; NP_001075091: p.Ser198ArgfsTer99) resulting in a mutant protein of 296 residues. In comparison to the normal 287 amino acid-long DLX3 protein, the C-terminal transactivation domain of the WT protein is replaced by a 99 peptide with no similarities to known proteins""." 9913
OMIA:000185 "From sequencing of the most likely comparative functional candidate gene, Anistoroaei et al. (2013) reported the causal mutation to be ""a base deletion (c.9468delC) in exon 40 of LYST, which causes a frameshift and virtually terminates the LYST product prematurely (p.Leu3156Phefs*37)""." "Using two microsatellites derived from a contig that includes the most likely comparative functional candidate gene (LYST), Anistoroaei et al. (2013) linkage-mapped the microsatellites, and hence LYST, in American mink to the centromeric region of chromosome NVI2. These authors also reported that the ""physical locations [of the microsatellies] also were confirmed on the basis of sequence homology aided by the Zoo-FISH data"" (Hameister et al., Chromosome Research 1997, 5, 5–11; Graphodatsky et al. 2000 Cytogenetics and Cell Genetics 90, 275–8)" 452646
OMIA:001000 9796
OMIA:000426 "Aware that the molecular cause of colour-sidedness in cattle (OMIA 001576-9913) results from reciprocal translocation between segments on chromosomes BTA6 (containing the KIT gene) and BTA29, Venhoranta et al. (2013) built on their mapping results (above) with cytogenetic and PCR analyses, and concluded ""that homozygosity of a ~500 kb chromosomal segment translocated from BTA6 to BTA29 (Cs29 allele) is the underlying genetic mechanism responsible for gonadal hypoplasia. The duplicated segment includes the KIT gene that is known to regulate the migration of germ cells and precursors of melanocytes. This duplication is also one of the two translocations associated with colour sidedness in various cattle breeds.""" "By conducting a GWAS on 21 affected and 75 control Northern Finncattle and Swedish Mountain cattle, each genotyped with the Illumina BovineHD SNp chip (yielding 647,971 informative SNPs), Venhoranta et al. (2013) mapped this disorder to chromosome BTA29. Further testing identified a 2.81Mb region between 17.69 Mb and 20.50 Mb. A copy number variant (CNV) analysis identified ""a CNV segment on BTA6, extending from 71.60 Mb to 72.13 Mb and containing the KIT gene"" and another on BTA29, but both of these were thought to reflect associations with the extent of white coat colour rather than the disorder." 9913
OMIA:000452 By cloning and sequencing a very likely candidate gene (based on knowledge that the disorder is due to aberrant expression of the enzyme aromatase) Matsumine et al. (1991) showed that the disorder is due to the terminal repeat sequence of a retrovirus that has been inserted into the 5' promoter region of the aromatase gene. This terminal repeat has a promoter of its own, which causes the aromatase gene to be switched on in atypical places, such as the skin of both sexes, giving rise to the henny-feathering trait in males. The actual peptide produced by the mutant allele is exactly the same as that produced by the normal allele, as we would expect for such a mutation. This disorder is the first insertion mutation documented in any domesticated species of animal. The Hf locus is located on the long arm of chromosome 1. 9031
OMIA:000246 "Excluding variants found in breeds that do not show this trait, Daetwyler et al. (2014) narrowed the field down to ""a missense mutation in KRT27 (c.276C>G; p.Asn92Lys; g.41636961C>G on BTA19; ss699911276)"". Strong supporting evidence of the causality of this mutation was found by studying its presence in numerous bulls of the Montbeliarde breed (in which the trait occurs, and which, like Fleckvieh, derives from the Simmental breed) compared with straight-hair breeds." Utilising imputation of sequence variants from the 1000-bull-genome project into each of 3,222 Fleckvieh bulls, each of which had been assessed for the proportion of daughters showing the curly hair trait, Daetwyler et al. (2014) mapped this trait to clusters of keratin genes on chromosomes BTA5 and BTA19. 9913
OMIA:001438 "By sequencing the positional candidate MLPH gene (see mapping section above) in silverblue, violet and wild-type mink, Cirera et al. (2013) ""identified two deletions of the entire intron 7 and of the 5′ end of intron 8 in the sequence of the Silverblue MLPH gene"". Investigation of MLPH mRNA revealed that ""the Silverblue animals completely lack exon 8, which encodes 65 residues, of which 47 define the Myosin Va (MYO5A) binding domain. This may cause the incorrect anchoring of the MLPH protein to MYO5A in Silverblue animals, resulting in an improper pigmentation as seen in diluted phenotypes."" Interestingly, even though the silverblue allele lacks the entire exon 8, it has ""retained part of the intron 8 in the coding region. This introduces a stop codon, leading to a truncated protein 284 residues long that is lacking almost all MYO5A Va and all actin-binding domains"". In addition, the authors reported that ""in the MLPH mRNA of wt, Violet and Silverblue phenotypes, part of intron 8 is retained resulting in a truncated MLPH protein, which is 359 residues long in wt and Violet and 284 residues long in Silverblue.""" "Anistoroaei and Christensen (2007) linkage-mapped this locus to chromosome NVI13, and showed that this locus was coincident with ""A Canis familiaris BAC clone containing the melanophilin gene (which generates 'silver-like' phenotype in dog)"", strongly suggesting that the silver locus in American mink is the MLPH locus. Using three microsatellites from a contig containing MLPH, Cicera et al. (2013) confirmed these results by linkage-mapping all three markers to the appropriate region of chromosome NVI3. They also reported physically mapping one of the microsatellites to NVI3q1.3-2.2." 452646
OMIA:000405 "Karageorgos et al. (2011) reported this disorder in Southdown sheep in Australia being due to two ""missense mutations c.1142G>A (p.C381Y) and c.1400C>T (p.P467L)"" in the gene for β-glucocerebrosidase (GBA). This gene is in the pipeline for addition to the NCBI gene list." 9940
OMIA:000236 "In December 2012, investigators from the Institute of Genetics at the University of Bern announced they had discovered a causal mutation for this disorder, and began offering a DNA test for it (See Genetic Testing section): a pdf describing their discovery is available from http://www.genetics.unibe.ch/unibe/vetmed/genetic/content/e2885/e3121/e186705/files186706/Interpretation_CMO_Gentest_e_eng.pdf. Thanks to Lotte Kirkegaard and Frank Coopman for bringing this to the attention of FN. As soon as the results are published, they will be included in this entry.
Hytönen et al. (2016): the likely causal mutation in West Highland White Terriers, Cairn Terriers and Scottish Terriers is a splicing variant ""c.1332C>T in exon 15 of SLC37A2 . . . The mutant T allele eliminates a potential binding site for the splicing factor ASF/SF-2""." 9615
OMIA:002043 Charlier et al. (2016): frameshift p.Leu38Argfs∗25 9913
OMIA:001617 32536
OMIA:000375 "Li et al. 92016): ""The c.995G>A mutation, which results in the amino acid substitution of Arg332His, was completely associated with the spot phenotype""." 8839
OMIA:000194 By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Dennis et al. (1989) reported the causative mutation as a C>T transition, altering arginine-86 (CGA) to a nonsense codon (TGA) (Mohammad Shariflou 10/11/2006; FN 19 Sept 2012). 11q28 9913
OMIA:002096 "Bauer et al. (2017): ""Whole genome sequencing of two affected horses, two obligate carriers, and 75 control horses from other breeds revealed a single non-synonymous genetic variant on the chromosome 7 segment that was perfectly associated with NFS. The affected horses were homozygous for ST14:c.388G>T, a nonsense variant that truncates more than 80% of the open reading frame of the ST14 gene (p.Glu130*). The variant leads to partial nonsense mediated decay of the mutant transcript.""" """Genotyping of 4 affected horses and 4 obligate carriers . . . by GeneSeek/NeoGene on the Affymetrix equine 670 k SNP array containing 670,796 evenly distributed markers"" enabled Bauer et al. (2017) to map ""the disease causing genetic variant to two segments on chromosomes 7 and 27 in the equine genome""." 9796
OMIA:001292 "After genotyping 7 affected Grehounds and 17 normal related Greyhounds with the 50K dog SNP chip, Drögemüller et al. (2010) used homozygosity mapping to identify the candidate 19.5 Mb region on chromosome CFA13. By sequencing the most likely candidate gene in this region, they identified the causative mutation as a 10 bp deletion in exon 15 of the NDRG1 gene (c.1080_1089del10).
Bruun et al. (2013) investigated the same disorder in Alaskan Malumutes and reported a novel mutation in the same gene: ""The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution."" The causative variant in the Alaskan Malamute is c.293G>T." 9615
OMIA:001623 "Ramunno et al. (2001) reported a null allele of the goat alpha s2-casein gene (CSN1S2) having ""a G-->A transition at nucleotide 80 of the 11th exon which creates a stop codon and could be responsible for the absence of the alpha s2-casein in goat milk""." 9925
OMIA:002111 "Hollmann et al. (2017): ""Whole genome re-sequencing of one case and four relatives showed a nonsense mutation (g.5995966C>T) in the PZP-like, alpha-2-macroglobulin domain containing 8 (CPAMD8) gene leading to a premature stop codon (CPAMD8 p.Gln74*)""." "From a GWAS on 26 affected and 88 normal Red Holstein Friesians, each genotyped with the Illumina BovineSNP50 BeadChip, yielding 46,075 informative SNPs, Hollmann et al. (2017) observed ""a significant association on bovine chromosome 7 at positions 6,166,179 and 12,429,691""." 9913
OMIA:000963 "Duchesne et al. (2006) identified a CpG/ApT non-conservative substitution in exon 33 (C4863A, G4864T) of the bovine LRP4 gene, which segregates perfectly with the disorder in a Holstein pedigree.
Johnson et al. (2006) reported a different mutation in the same gene in Angus cattle: ""a G to A transition at the first nucleotide in the splice donor site of intron 37 completely disables this splice site. The abnormal splicing that is caused by this mutation predicts the generation of a dysfunctional membrane-anchored receptor lacking the normal cytoplasmic domain.""" "Charlier et al. (1996) conducted a genome scan with 213 microsatellite markers genotyped on just 12 syndactylous (mule foot) animals and on a DNA pool of 10 unrelated non-affected animals from the same breed. Identity-by-descent mapping (""searching for shared homozygous haplotypes among affected individuals"") identified a single region on each three chromosomes as being significant. Genotyping an additional 29 animals from the same pedigree, followed by a conventional linkage analysis, mapped the disorder to the telomeric end of chromosome BTA15.
In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) mapped this disorder to BTA15 at 76-82Mb (UMD 3.0 genome assembly), consistent with the results of Charlier et al. (1996)." 9913
OMIA:000424 "Veenboer and de Vijlder (1993) reported the causal mutation in the goat TG gene as being ""a C-->G point mutation [at nucleotide 945] in exon 8 causing a change from TAC (Tyr)-->TAG (termination signal) at amino acid position 296.""" 9925
OMIA:001466 The causative mutation in Labrador retrievers, Chesapeake Bay retrievers and curly-coated retrievers is a G to T substitution in exon 6 that changes the amino acid codon from arginine to leucine (R256L) in a highly conserved region of DNM1 (Patterson et al., 2008). A genome-wide scan with 459 microsatellites in six families of Labrador Retrievers mapped the disorder to 60.4Mb on CFA9 (Patterson et al., 2008) 9615
OMIA:002105 Tsuboi et al. (2017): PLA2G6 c.1579G>A; p.T526A 9615
OMIA:000499 "A genome scan with microsatellites evenly spaced throughout the genome at around 20cM, conducted by Haslerrapacz et al. (1998) on 65 backcross pigs segregating for this disorder, showed that the gene for this disorder in pigs maps near to the centromere of chromosome 2, which is homologous to the region of human chromosome 19 containing the gene for low-density lipoprotein receptor (LDLR), a strong candidate for involvement in this disorder. Sequence analysis of the LDLR gene from homozygous normal and affected pigs showed that the disorder is due to a single missense mutation (resulting in the amino-acid substitution Arg84Cys). The causal mutation was thus identified via the comparative positional candidate gene approach.
In a proof-of-principle study, Carlson et al. (2012) used Transcription Activator-Like Effector Nucleases (TALENs) to create cloned pigs with a range of mutations in the porcine LDLR gene, namely 289_290ins34, 285_287delATG, 211_292del128, 289_290del10 and 289_290insA. The phenotypes of these mutant pigs were not reported in this paper.
Using homologous recombination to insert a premature stop codon and a neomycin-resistance casette into exon 4 of the LDLR gene in Yucatan miniature pigs, followed by somatic cell nuclear transfer and the mating of heterozygotes, Davis et al. (2014) created Yucatan miniature pigs completely lacking any functional LDLR. The authors report that this ""new model of cardiovascular disease could be an important resource for developing and testing novel detection and treatment strategies for coronary and aortic atherosclerosis and its complications.""" 9825
OMIA:001684 "Gandolphi et al. (2013) reported the first Genome-Wide Association Study (GWAS) in cats, which led them to the discovery of the causal mutation for for curly/woolly hair in the Cornish Rex breed: a ""4 bp deletion in exon 5 of the LPAR6 [which encodes lysophosphatidic acid receptor 6], c.250_253_delTTTG, which induces a premature stop codon in the receptor . . . The mutation is fixed in Cornish Rex, absent in all straight haired cats analyzed, and is also segregating in the German Rex breed.""" 9685
OMIA:001400 "Zhao et al. (2012) reported the causal mutation as being ""a one base pair deletion, T (JN108880:g.25513delT) at the 107 bp position of exon 3"" of the SLC13A1 gene." Using the ovine SNP50 BeadChip, Zhao et al. (2012) mapped this disorder to a 1Mb region on chromosome OAR4. 9940
OMIA:001260 Kukekova et al. (2009) showed that rod-cone dysplasia type 2 (rcd2) in Collies is due to an insertion mutation in the canine homologue of the human RD3 gene, previously known as C1ORF36. 9615
OMIA:001374 "Pelé et al. (2005) determined the molecular basis of this disorder by adopting a comparative positional cloning approach. Having mapped the canine disorder as described in the Mapping section above, they then studied the 208 human genes that are located in the orthologous region of chromosome HSA10p. Based on tissue expression and sequence motif, the most likely of these 208 genes was PTPLA (protein tyrosine phosphatase-like, member A). Sequencing of the canine PTPLA gene revealed the causative mutation as an insertion of a ""tRNA-derived short interspersed repeat element (SINE)"" in exon 2 (""PTPLA*g9459-9460ins236"") which ""has a striking effect on the maturation of PTPLA mRNA, whereby it can be spliced out, partially exonized or involved in multiple exon-skipping. As a result, the amount of wild-type transcripts falls to 1% in affected muscles.""" "Conducting a genome scan with 66 microsatellites on a four-generation pedigree that ""comprised 40 dogs among which 20 were affected (12 females and 8 males)"" Tiret et al. (2003) mapped this disorder to the centromeric region of chromosome CFA2. Subsequent fine mapping reduced this to an ""18.1-cM interval between markers FH2087U and AHT132"". Subsequent FISH-mapping ""established orthology between the centromeric region of CFA2 and the GDI2-cREM human segment (HSA10p15/HSA10p12.1-p11.1)"". " 9615
OMIA:001564 "Boudreaux and Martin and (2011) reported the causal mutation as being ""a 3 base-pair deletion predicted to result in elimination of a serine from the extracellular domain was identified in the gene encoding P2RY12, an ADP receptor protein located on platelet membranes""." 9615
OMIA:002053 Exome sequencing by Sasaki et al. (2016) within the candidate region (see Mapping section) revealed a likely causal missense variant: g.62382825G > A, p.Pro372Leu) in exon 10 of solute carrier family 12, member 1 (SLC12A1). Using autozygosity mapping, Sasaki et al. (2016) mapped this diorder in Japanese Black cattle to a 3.52 Mb region on bovine chromosome BTA10. 9913
OMIA:001919 "Among the 21 positional candidate genes in the region to which this disorder was mapped (see Mapping section), Wolf et al. (2014) identified two (DLX5 and DLX6) as functional candidates (being transcription factors involved in craniofacial development; and containing causal mutations in mice). Sanger sequencing of the coding regions and conserved introns of these two genes in 1 affected and 1 unaffected Nova Scotia Duck Tolling Retriever revealed a ""2056 bp [LINE-1] insertion . . . within a highly conserved region of DLX6 intron 2 at cfa14.25016716"" as the most likely causal mutation. As reported by the same authors, ""The LINE-1 insertion is predicted to insert a premature stop codon within the homeodomain of DLX6."" Genotyping for this mutation in a range of families in which the disorder is segregating confirmed it as causal." From a GWAS conducted on 14 affected and 72 normal Nova Scotia Duck Tolling Retrievers, each genotyped with the Illumina CanineHD BeadChip (yielding 109,506 informative SNPs), Wolf et al. (2014) mapped this disorder in this breed to a 5.1Mb region (24.2 Mb to 29.3 Mb; CanFam2.0) on chromosome CFA14. 9615
OMIA:001471 The causative variant is a missense c.152T>G transversion causing a p.M51R methionine to arginine substitution in ATF2 (Chen et al., 2008). The mutation lies in a hydrophobic docking site for protein kinases that activate ATF2. Mutant ATF2 retains partial activity (Chen et al., 2008). The locus for NEWS was mapped by linkage analysis with microsatellites in a large family with 20 affected dogs. Maximum LOD scores exceeding 7 were obtained on CFA36 between markers UMC0297 and REN252E18 (Chen et al., 2008). The ATF2 gene was identified as a positional and functional candidate gene within the 2.87 Mb critical interval. 9615
OMIA:002013 "Regarding the deletions mentioned in the Mapping section, Rafati et al. (2016) reported that ""One of the identified deletions removes the entire coding region of the short stature homeobox (SHOX) gene and both deletions remove parts of the cytokine receptor-like factor 2 (CRLF2) gene located downstream of SHOX."" The same authors then ""sequenced bacterial artificial chromosome (BAC) clones by single-molecule real-time (SMRT) sequencing technology. This considerably improved the assembly and enabled size estimations of the two deletions to 160-180 kb and 60-80 kb, respectively. Complete association between the presence of these deletions and disease status was verified in eight other affected horses.""" "Rafati et al. (2016) ""performed whole genome resequencing of six SA [skeletal atavism] cases and a pool of control horses and use this data to show that skeletal atavism is associated with two, partially overlapping, large deletions on sequence scaffolds not assigned to any chromosome in the EquCab2.0 genome assembly"". These ""two partially overlapping large deletions [are] in the pseudoautosomal region (PAR) of chromosome X/Y""" 9796
OMIA:000307 "Of the 137 genes annotated in the candidate region on CFA9 (see Mapping section above), only one was a likely candidate, namely ""LHX3, a transcription factor essential for pituitary gland formation"" (Voorbij et al., 2011). Sequencing revealed a causative mutation as ""a deletion of one of six 7 bp repeats in intron 5 of LHX3, reducing the intron size to 68 bp . . . An exon trapping assay indicated that the shortened intron is not spliced efficiently, probably because it is too small."" (with thanks to Frank Coopman for alerting FN to this discovery in Sep 2012).
Voorbij et al. (2011) also mentioned briefly that one of their dwarfs was a compound heterozygote for the above deletion and ""for an insertion of an ACA trinucleotide sequence . . . . The insertion occurred at a site of two ACA triplets that are normally present in exon 5 (NM_001197187, c.545_547dupACA). The result for the open reading frame was an insertion of an AAC codon for asparagine at position 182 of the LHX3b protein isoform (p.N182dup), which is located in the first α-helix of the homeodomain of LHX3. The triplet insertion and the heterozygosity of the dwarf were confirmed by sequence analysis of exon 5 from genomic DNA . . . . The insertion is situated close to intron 5 and can be amplified as part of the same fragment."" Thanks to Frank Coopman and Jonas Donner for pointing out this second mutation to FN.
Voorbij et al. (2014) reported that the same causal 7bp deletion in two breeds resulting from crossing German Shepherd dogs with wolves: ""Saarloos and Czechoslovakian wolfdog dwarfs have the same 7 bp deletion in intron 5 of LHX3 as do German Shepherd Dog dwarfs.""" "Using a genome-wide homozygosity-mapping strategy with 256 microsatellite markers, followed by fine-mapping with another 49 microsatellites, Voorbij et al. (2011) mapped this disorder to a region on chromosome CFA9 flanked by ""markers REN256F13 at position 49.5 Mb and REN177B24 at 54.1 Mb"".
By conducting a GWAS on 4 affected and 193 control German Shepherd dogs, each genotyped with the Affymetrix v2 canine SNP chip (Yielding 48,415 SNPs for the analysis), Tsai et al. (2012) confirmed the region on chromosome CFA9, which (they noted) includes a potential candidate gene, LHX3 (the same as was identified by Voorbij et al. (2011): see Molecular section below." 9615
OMIA:001365 "A causative mutation for this disorder was identified via a comparative positional cloning approach. First, as described in the Mapping section, a genome scan showed that the disorder locus is in a region of chromosome CFA29. The homologous region of the human genome (HSA8q21-22) contains the gene for cyclic nucleotide-gated channel β-subunit (CNBG3), mutations in which cause a very similar disorder in humans (see the OMIM entry above). Sequencing of this strong comparative positional candidate gene enabled the same authors to report that this disorder in Alaskan Malamute [AM]-derived dogs is due to a ""deletion removing all exons of canine CNGB3"".
Interestingly, Yeh et al. (2013) reported homozygosity for exactly the same deletion mutation in affected dogs of the miniature Australian Shepherd [MAS] breed; and heterozygosity for exactly the same deletion mutation in two other breeds (Siberian husky and Alaskan sled dogs). Importantly, these same authors concluded ""All affected alleles were shown to be IBD, strongly suggesting an affected founder effect. Since the MAS is not known to be genetically related to the AM, other breeds may potentially carry the same cd-allele and be affected by achromatopsia.""" Sidjanin et al. (2002) conducted a genome scan with microsatellites, and identified one microsatellite on CFA29, namely C29.002, completely linked to the disorder locus, with recombination fraction = 0 at a LOD score of 24.68. 9615
OMIA:000827 "Kunz et al. (2016) reported a likely causal mutation as ""a missense mutation (p.S568N, c.G1703A; [Chr4: 49,878,773 bp, rs800397662]) in the PNPLA8 gene that encodes patatin-like phospholipase domain containing 8""." "In one of the very early genome scans, Georges et al. (1993) genotyped 33 affected Brown Swiss, plus (where possible) their sires, dams and normal siblings, with ""82 multisite haplotypes . . . , 38 variable number of tandem repeat markers . . . , and 233 bovine dinucleotide microsatellites"". The 78th microsatellite tested in two-point linkage analysis, namely TGLA116, showed a significant recombination fraction of 3% with the disorder. No other markers showed any linkage. Subsequent somatic-cell-hybrid mapping enabled TGLA116 to be allocated to bovine synteny group 13.
In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) mapped this disorder to BTA4 at 45-56Mb (UMD 3.0 genome assembly).
By conducting a GWAS on 20 carriers and 51 normal Brown Swiss, each genotyped with the Illumina BovineHD assay (yielding 733,937 informative SNPs), and subsequent fine-mapping, McClure et al. (2013) refined the mapping of this disorder to a 252 kb haplotype on chromosome BTA4, which will provide greater accuracy for carrier detection.
In their table of reduced-fertility haplotypes, Cole et al. (2014) list the ""Weaver"" haplotype as haplotype BHW (for Brown Swiss/Haplotype/Weaver)." 9913
OMIA:000328 In 2012, Zhou et al. showed that the situation described in the Species-specific section above is, indeed, the case: the disorder in Dorper sheep is due to a nonsense mutation in exon 2 of the gene encoding that procollagen proteinase. Unhelpfully, the gene is called ADAM metalloproteinase with thrombospondin type I motif, 2 (ADAMTS2). 9940
OMIA:001586 "By cloning and sequencing a very likely candidate gene (based on the observation that ""The domestic cat has a significantly lower capacity to glucuronidate planar phenolic xenobiotics compared with most other mammalian species""), Court and Greenblatt (2000) showed that all cats are homozygous for a mutated form of the UGT1A6 gene that encodes UDP-glucuronosyltransferase 1A6, and hence completely lack this most important phenol-detoxification enzyme. From comparative analyses, Shrestha et al. (2011) concluded that the mutated form of the gene was fixed between 35 and 11 million years ago, resulting in all Felidae being homozygous for the mutated gene and hence the lack of the enzyme. As Shrestha et al. (2011) note, this accounts for felid's ""remarkable sensitivity to the adverse effects of phenolic drugs, including acetaminophen and aspirin, as well as structurally-related toxicants found in the diet and environment"". The authors hypothesise that the loss of this gene may have been tolerated as felids became more carnivorous." 9685
OMIA:001772 By whole-genome resequencing one of the affected dogs at 30X coverage, Frischknecht et al. (2013) identified 92 non-synonymous variants in the 4.44 Mb region mentioned in the Mapping section above. Two non-synonymous variants in the critical interval were perfectly associated with SD2 in larger cohorts of dogs. Of the two that were perfectly associated with the trait the most likely causative variant is COL11A2:c.143G>C, which is predicted to result in p.R48P on the protein level. This amino acid exchange is at an evolutionary conserved position at the N-terminus of the collagen molecule, before the beginning of the triple-helical domain. It is assumed to have only a minor impact on COL11A2 function as Col11a2 knock out mice and human patients with other COL11A2 mutations show more severe phenotypes. SD2 was mapped to CFA 12 in a genome-wide association study (GWAS) using 23 cases and 37 controls. The best raw p-value in this analysis was 4.4E-16. The critical interval defined by homozygosity mapping spanned 4.44 Mb. This analysis revealed that 22 out of the 23 initially considered cases were homozygous for a shared haplotype in the critical interval. The 23rd case did not carry this haplotype and was assumed to represent a phenocopy (Frischknecht et al. 2013). 9615
OMIA:001977 "As reported by Wiik et al. (2015), ""Sequencing of [the above candidate] gene identified a 4-bp deletion in exon 9 (c.1752_1755delAACT), leading to a frameshift and a premature stop codon"". Pedigree analysis indicated that this is a likely causal mutation in some, but not all, Sheltie families." "As reported by Wiik et al. (2015), ""Using genome-wide association with 15 Shetland Sheepdog (Sheltie) cases and 14 controls, we identified a novel PRA locus on CFA13 (Praw = 8.55 × 10(-7) , Pgenome = 1.7 × 10(-4) ). CNGA1, which is known to be involved in human cases of retinitis pigmentosa, was located within the associated region and was considered a likely candidate gene.""" 9615
OMIA:001302 "By cloning and sequencing a very likely candidate gene (based on knowledge of the receptor that results in susceptibility), Klucking et al. (2002) reported that the tvb gene ""is a tumor necrosis factor receptor (TNFR)-related death receptor that is most similar to the mammalian TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5"". They also showed that resistance is due to a nonsense mutation (C172T) that results in a ""severely truncated protein product"". The TVB gene is now known as TNFRSF10B." 9031
OMIA:000341 "In a sign of the times, Menoud et al. (2012) needed only three affected Rotes Höhenvieh calves to identify the causative mutation of this disorder as being a ""SNP in the bovine COL7A1 exon 49 (c.4756C>T) . . . which causes a premature stop codon which leads to a truncated protein representing a complete loss of COL7A1 function (p.R1586*)""
Independently of the above discovery, Pausch et al. (2016) discovered exactly the same likely causal variant (now recognised to be BTA22:g.51873390C>T [UMD3.1]; c.4762C>T; p.Arg1588X) in the Vorderwald breed, for which there is no documented admixture with the Rotes Höhenvieh breed, leading them to conclude ""that deleterious alleles may segregate across cattle breeds without any documented admixture""." "Menoud et al. (2012) ""localized the causative mutation to an 18 Mb interval on chromosome 22 by homozygosity mapping""." 9913
OMIA:001452 "Following hot on the heels of the mapping of this disorder, Fasquelle et al. (2009) showed it to be due to a frameshifting 2-bp deletion (c.2904-2905delAG) in the MRC2 gene (encoding mannose receptor C type 2).
Following the publication of the 2009 paper, 18 new cases with exactly the same clinical signs were detected, and were all shown by Sartelet et al. (2012) to be NOT homozygous for this (recessive) mutation, but instead to be heterozygous for this mutation. How could this be? Why would heterozygotes for a recessive disorder show all the clinical signs usually seen in homozygotes? Detailed investigation by Sartelet et al. (2012) of these 18 cases showed each of them to be a compound heterozygote for the c.2904-2905delAG mutation and a newly identified mutation, namely c.1906T>C, in the same gene. The former mutation results in no functional peptide, and the latter mutation results in illegitimate oligomerization of the peptide. Consequently, compound heterozygotes for these two mutations have no fully functional gene product, and hence are affected with the disorder. " "In a pioneering use of tens of thousands of SNP markers (""using either the 25K Affymetrix SNP panel or a custom-made 60K Illumina panel""), Charlier et al. (2008) identified a single 2.42 Mb region on BTA19 in which 8 affected calves were significantly more homozygous for the same allele at each of many SNPs, when compared with 14 normal controls. " 9913
OMIA:002095 "Wielaender et al. (2017): ""a 4-bp deletion in the exon 2 of the DIRAS1 gene (c.564_567delAGAC . . . CanFam3 . . . , resulting in a frameshift and a stop loss. . . . The genotyping of the DIRAS1 deletion in 14 clinically verified RR cases and 26 controls revealed a homozygous mutant genotype in all cases, a heterozygous genotype in the obligate carriers, and the homozygous wild-type genotype in controls.""" 9615
OMIA:001572 "By sequencing the most likely functional candidate gene from the candidate region (see Mapping section), Downs et al. (2011) identified a causal mutation as ""a frame shift mutation [in SLC4A3] caused by the insertion of a single cytosine in exon 16 (c.2601_2602insC; CFA37:29,147,633). It is predicted to cause a premature stop codon in exon 18 (p.E868RfsX104) possibly resulting in degradation of the mRNA by nonsense-mediated decay (NMD) or a truncated protein product"". Although this mutation is causal in the families in which it exists, it does not account for all cases of the disorder in this breed." By conducting a GWAS on 27 affected and 19 control Swedish Golden Retrievers, each genotyped with the CanineSNP20 BeadChip (yielding 14,389 informative SNPs for analysis), Downs et al. (2011) mapped this disorder to a region on chromosome CFA37. Subsequent homozygosity mapping narrowed the region to 644kb, which contains 27 genes. 9615
OMIA:002081 In a textbook example of how to make use of clinical information to identify a comparative candidate gene (based on the homologous human disorder) namely KRT5 (keratin 5), Ford et al. (2005) showed that this disorder in the offspring of a Friesian-Jersey bull is due to a 4051G>A base substitution in the bovine KRT5 gene, leading to an E478K amino-acid substitution. The bull turned out to be mosaic for a de novo mutation. 9913
OMIA:000629 Noting that mutations in the genes for endothelin 3 (EDN3) or its receptor (EDNRB) are responsible for similar disorders in humans and rodents, Santschi et al. (1998), from the University of Minnesota, sequenced cDNA from 22 affected foals, their parents, and some solid-colour normal controls, all registered with the American Paint Horse Association. There was no variation in the EDN3 gene, but a di-nucleotide substitution (TC>AG) at nucleotides 353-354 of the gene for EDNRB, resulting in an Ile118Lys amino-acid substitution, segregates perfectly with LWFS, thereby providing a molecular explanation for the disorder in American Paint horses. In quick succession, two other research groups reported similar findings: Metallinos et al. (1998), from the University of California, found the same mutation in other US horses; and Yang et al. (1998) found the same mutation causing the same disorder in Australian horses. Interestingly, both American studies found that some non-overo horses are carriers, suggesting that the mutation has incomplete penetrance. 9796
OMIA:001222 Lyons et al. (2016): c.577C>T; a predicted p.Arg193* To map this disorder, Alhaddad et al. (2014) genotyped each of 106 animals (comprising 37 affecteds and 69 controls) from a colony of Persian cats segregating the disorder (established by Rah et al., 2005) with the illumina Infinium Feline 63 K iSelect DNA array, yielding 47,907 informative SNPs. Using these data, they then conducted a genome-wide linkage analysis, and three GWAS, namely a transmission disequilibrium test (TDT) on 33 discordant trios, a TDT among sib-pairs on 33 discordant sibs, and a case-control association analysis on all 106 animals. All four analyses highlighted an ~ 1.75 Mb region on chromosome FCA E1. Haplotype analysis reduced this region to ~1.3 Mb. The authors noted that this region contains several potential comparative positional and functional candidate genes. 9685
OMIA:001566 Diribarne et al (2011) showed that the r1 rex hair coat phenotype in rabbits is due to a single nucleotide deletion in exon 9 of the LIPH gene. Castle and Nachtsheim (1933) showed that r1 rex is linked to r2 rex (OMIA 002005-9986) with a recombination frequency of 10-12%. These same authors showed that the third type of rex in rabbits, r3 (OMIA 002006-9986), segregates independently of r1 and r2. 9986
OMIA:001592 By sequencing the most likely positional candidate gene in the candidate region they had identified (see Mapping section), Gill et al. (2012) reported that this disorder in Cavalier King Charles Spaniels is due to a 15.7kb deletion in the BCAN gene, which encodes brain-specific extracellular matrix proteoglycan brevican. By sequencing 5 affected dogs within their candidate region (see Mapping section), Forman et al. (2012) reported the same mutation. "By conducting a GWAS on 5 affected, one obligate carrier and 9 control Cavalier King Charles spaniels, each of which had been genotyped with the Affymetrix Canine SNP Array version 2 (yielding 58,873 informative SNPs for analysis), Gill et al. (2012) mapped this disorder to a 3.48Mb region on chromosome CFA7.
By conducting a GWAS on 31 affected and 38 control Cavalier King Charles Spaniels, each genotyped with the Illumina Canine HD SNP chip (yielding 91,427 SNPs for analysis), Forman et al. (2012) highlighted the same region on chromosome CFA7 as had been reported by Gill et al. (2012). " 9615
OMIA:000259 9825
OMIA:001876 "Sequencing of the two candidate genes in this region led Goldstein et al. (2013) to the discovery of the causal mutation as a stop-loss or extensionl base substitution in the SAG gene (encoding S-antigen): a ""tyrosine to cysteine transition mutation at position CFA25:47,845,680 (c.1216T>C . . .) that changed the normal stop codon to code for the amino acid arginine, which would result in a deduced addition of 25 amino acids (p.*405Rext*25) to the normal 405 amino acid protein"". " A GWAS conducted by Goldstein et al. (2013) on 6 affected and 3 control Basenjis, each genotyped with the Illumina HD Canine SNP Chip comprising 173,662 SNPs, implicated regions on chromosomes CFA4, CFA13 and CFA25. Haplotype analysis suggested the CFA25 region as the most likely candidate region. Homozygosity mapping analysis confirmed the CFA25 region as most likely. 9615
OMIA:000364 "Bender et al. (2015) characterised the obvious functional and comparative candidate gene for this disorder, namely the gene for factor XII, in cats: ""Fourteen exons ranging in size from 57 to 222 base pairs were confirmed spanning 8 Kb on chromosome A1. The 1828–base pair feline FXII messenger RNA (mRNA) sequence contains an open reading frame that encodes a protein of 609 amino acids with high homology to human FXII protein."" Subsequent sequencing in normal and affected cats identified a ""single base deletion in exon 11 of the FXII coding gene in our colony of cats results in deficient FXII activity. Translation of the mRNA transcript shows a frame shift at L441 (C441fsX119) resulting in a nonsense mutation and a premature stop codon with a predicted 560–amino acid protein. The mutant FXII protein is truncated in the 3′ proteolytic light chain region of the C-terminus, explaining its loss of enzymatic activity.""
By sequencing the most likely candidate gene in 6 Japanese domestic short-hair cats (2 cats with severely reduced FXII activity (7.1 % and 9.3 %, respectively) and 4 cats with moderately reduced FXII activity (range 36.0 to 46.3 %)), Maruyama et al. (2017) identified a new likely causal variant in exon 13 of the F12 gene: ""Cats with severely reduced FXII activity were homozygous"" for a missense mutation c.1631G>C, p.G544A; ""Cats with moderately reduced FXII activity were heterozygous for this mutation"". These authors also reported that ""Expression studies revealed reduced secretion of p.G544A mutant FXII protein from transfected HEK293 cells compared with wild type FXII.""" 9685
OMIA:001660 "In the course of investigating BIN1 mutations as a cause of centronuclear myopathy (CNM) in humans, Böhm et al. (2013) searched for potential animal models of CNM, and alighted upon Inherited Myopathy of Great Danes as a likely model. Having five affected dogs from Canada, USA and UK at their disposal, Böhm et al. (2013) identified a causal mutation as ""a homozygous AG to GG substitution of the BIN1 exon 11 acceptor splice site in five dogs from Canada, US and UK (IVS10-2A>G"". The authors also reported that ""The BIN1 IVS10-2A>G mutation was not found in 112 healthy Great Danes and in 35 dogs from 12 other breeds, strongly suggesting its pathogenicity."" However, they did note that ""Some dogs of our IMGD cohort were found to be negative for BIN1 mutations, suggesting that IMGD encompasses several disorders with similar clinical and overlapping histopathological features"". " 9615
OMIA:001423 Chu et al. (2007) showed that the fecundity of the Small Tailed Han breed is due to the segregation of the FecB(B) mutation (Q249R) in the BMPR1B gene (OMIA 000383-9940) and the FecX(G) mutation (Q239Ter) of the BMP15 gene (OMIA 000384-9940). 9940
OMIA:001697 "Sonstegard et al (2013) investigated the lethal Jersey haplotype, namely haplotype JH1 on chromosome BTA15 (see Mapping section). They first refined the haplotype ""to a 15-marker window (15,162,470 to 15,949,175)"" and then obtained whole-genome sequence from 11 bulls carrying this haplotype. Analysis of the sequence of these carriers in the candidate region revealed a ""high-impact stop-gain SNP located at position 15,707,169 on BTA15. This C-to-T transition SNP results in an Arginine to a stop codon in exon 3 of CWC15, the bovine protein CWC15 homolog of a spliceosome-associated protein . . . . This nonsense mutation would reduce the size of the CWC15 protein product from 231 amino acids in length to only 54 amino acids. A NCBI conserved domains search on the bovine CWC15 protein product reveals that this truncated protein would not have the conserved Cwf_Cwc_15 (pfam04889) domain present in the wildtype.""" Using genotype data from tens of thousands of North American Holsteins, Jerseys and Brown Swiss cattle each genotyped with approximately 50K SNPs on the BovineSNP50 BeadChip, VanRaden et al. (2011) identified five new recessive lethal haplotypes by searching for common haplotypes that are never homozygous in live animals. One of these haplotypes occurs in Jerseys only, and (following a convention proposed by breed-association staff) VanRaden et al. (2011) named it JH1, where J stands for Jersey and H for haplotype. It maps to chromosome BTA15, at 13-18Mb (UMD 3.0 genome assembly). 9913
OMIA:000059 Having a good idea of the map location of the gene responsible for this disorder in Brown Swiss cattle, Drogemuller et al. (2010) used sequence capture followed by resequencing to identify a single base insertion in the gene for sulfite oxidase (SUOX) as being causative for this disorder in this breed. (With thanks to Tosso Leeb). The synthesis of sulfite oxidase is dependent upon molybdenum cofactor (Moco), whose synthesis is dependent upon two peptides (MOCS1A and MOCS1B) that are encoded (via consecutive reading frames) by the gene MOCS1. Consistent with their mapping results, Buitkamp et al. (2011) have shown that arachnomelia in Simmental cattle is due to a 2-bp deletion in the MOCS1 gene (see OMIA 001541). Thus we have an excellent example of mutations in two genes involved in the same biochemical pathway giving rise to the same biochemical deficiency and hence the same clinical signs. This is the first example of this type of genetic heterogeneity to be documented in cattle. As stated by Buitkamp et al. (2011), arachnomelia is thus the first example in cattle of an oligogenic disorder. "Drogemuller et al. (2009) mapped this disorder in Brown Swiss cattle to a 7Mb region on chromosome BTA5. In stark contrast, Buitkamp et al. (2009) demonstrated that a locus for a similar defect in Simmental cattle maps to BTA23 (see OMIA 001541). (With thanks to Tosso Leeb). These results suggested the strong possibility of genetic heterogeneity for this disorder in cattle.
In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) confirmed the mapping of this disorder to BTA5, at 62Mb, in Brown Swiss cattle (UMD 3.0 genome assembly)." 9913
OMIA:000683 9615
OMIA:001315 "As reported by Neff et al. (2012), ""The SNP pattern [from the GWAS] suggested the presence of a spontaneous deletion"" which was confirmed by FISH analysis. Further analysis revealed a 130kb deletion which ""ablated all but the first exon of SLC13A1, a sodium/sulfate symporter responsible for regulating serum levels of inorganic sulfate"". " A GWAS with 173K SNPs by Neff et al. (2012) on 8 cases and 8 controls implicated a 1.19Mb haplotype at the terminal end of chromosome me CFA14, which included six coding sequences. 9615
OMIA:001362 Using the candidate gene approach, Wu et al. (2016; first published online in 2015) provided strong evidence that a 6bp deletion in TYRP1 (g.17599_17604del; p.M495_G496del) is the cause of the blond coat colour in Liangshan pigs. 9825
OMIA:000830 "Extensive molecular investigations have excluded the opsin gene as a candidate locus for this disorder in Miniature Poodles, English Cocker Spaniels or Labrador Retrievers (Gould et al., 1995).
In a GWAS on 9 affected, 4 obligate carriers and 10 control Papillon dogs, each genotyped with the Illumina Canine HD BeadChip (yielding 116,235 informative SNPs), Winkler et al. (2013) found no significant associations. They then tried homozygosity mapping, which yielded 13 candidate regions, four of which contained likely candidate genes. Subsequent haplotype analysis and comparative clinical phenotyping (in humans and mice) pointed to the region containing the CNGB1 gene. Sequencing of this gene revealed the causal mutation to be ""a complex mutation consisting of the combination of a one basepair deletion and a 6 basepair insertion was identified in exon 26 (c.2387delA;2389_2390insAGCTAC) leading to a frameshift and premature stop codon"".
A week later, Ahonen et al. (2013) reported a GWAS on 6 affecteds (4 Papillons, 2 Phalènes) and 14 normals (3 Papillons, 11 Phalènes), each genotyped with the same Illumina CanineHD BeadChip (yielding 109,022 informative SNPs), which implicated the same region on chromosome CFA2 as identified by Winkler et al. (2013). Sequencing then identified the same causal indel mutation, which they numbered slightly differently and placed in exon 25, namely c.2685delA2687_2688insTAGCTA, which creates a frameshift, leading to ""a premature stop-codon p.Tyr889Serfs*5 in an evolutionary conserved region"" of CNGB1." 9615
OMIA:000666 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous disorder in other species), Foureman et al. (2004) were the first to report a molecular basis of this disorder, as follows: ""When the DNA coding sequence from miniature pinschers affected with MPS VI was compared to the normal canine sequence, a single missense mutation (G to A) was identified. This mutation, occurring in exon V, replaces the tiny amino acid glycine with a bulky arginine in a highly conserved region of the protein and is found only in affected dogs.""
Jolly et al. (2012) reported a different mutation in a Miniature Poodle-type of dog: ""A novel homozygous 22 base pair (bp) deletion in exon 1 of this enzyme's [ARSB] gene was identified (c.103_124del), which caused a frameshift and subsequent premature stop codon.""" 9615
OMIA:000627 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Zhang et al. (1990) reported a nonsense mutation (248C>T) in the leader region of the gene for the E1 alpha subunit (BCKDHA) as the cause of the disorder in Poll Herefords.
A 1380C>T transition in the same gene was reported by Dennis and Healy (1999) to be responsible for the disease in Poll Shorthorns (Mohammad Shariflou 3/11/2006; FN 14/9/2011)." 9913
OMIA:001402 "By cloning and sequencing a very likely candidate gene (based on knowledge of the biochemistry and physiology of the disorder) Mealey et al. (2001) identified the causative mutation as a 4 bp deletion (c.296_299del4) in the ABCB1 (MDR1) gene, which encodes P-glycoprotein drug transporter (P-gp). The deletion causes a frame shift, introducing several stop codons, which cause premature protein truncation. P-gp is an ATP-driven drug transporter that binds a variety of drugs in the endothelial cells and transports them back into the blood, preventing them from diffusing into the brain. P-gp is expressed in brain capillaries, renal proximal tubules, liver, small bowel, colon, placenta, and brain endothelium. P-gp is also expressed at high levels in tumor cells, allowing them to resist a spectrum of chemotherapeutic drugs (Mealey et al., 2001, Gramer et al., 2011).
Han et al. (2010) reported a different causal mutation, c.73insAAT, in an ivermectin-sensitive Border Collie.
Alves et al. (2011) reported a base substitution (c.-6-180T>G) in intron 1 that ""was significantly more frequent in epileptic [Border Collies] resistant to [phenobarbital] treatment than in epileptic BCs responsive to PB treatment"".
" 9615
OMIA:001559 Silva et al. (2011) reported a missense mutation (c.1034T>G; p.Phe345Cys) in the GDF9 gene giving rise to increases of 82% and 58% for ovulation rate and prolificacy, respectively, compared with homozygous wild-type. 9940
OMIA:000438 "The causative mutation for this disorder was discovered via the candidate gene approach, by Evans et al. (1989), who reported that the mutant allele in the Chapel Hill colony is c.1477G>A, resulting in the substitution of glutamic acid for glycine at codon 379 in the factor-IX peptide. This particular site has been highly conserved throughout evolution: there is a glycine at this position in factor IX from human, pig and cattle. Not surprisingly, therefore, this single amino-acid substitution profoundly alters the tertiary structure of the factor-IX molecule, to the extent that no functional factor IX can be detected, which is unusual for a missense mutation .
In contrast, a different mutation causes the same disorder in Lhaso Apso dogs: Mauser et al. (1996) reported a deletion of bases 772-776 plus a C>T transition at base 777 in the Auburn colony.
In an affected Labrador Retriever, Brooks et al. (1997) reported a deletion of the entire gene.
Gu et al. (1999) reported two new mutations - an insertionin exon 8 and another deletion.
Brooks et al. (2003) reported a 1.5kb LINE1 insertion in exon 5 associated with a mild form of the disorder.
In Rhodesian Ridgebacks, Mischke et al. (2011) reported ""a G-A missense mutation in exon 7. This mutation results in a glycine (GGA) to glutamic acid (GAA) exchange [G244E] in the catalytic domain of the haemophilic factor IX""" From the results of planned matings, Brinkhous et al. (1973) showed that although the genes for both haemophilia A and haemophilia B are on the X chromosome, they are inherited independently. A similar situation exists in human. 9615
OMIA:001485 9913
OMIA:000102 "Hellström et al. (2010) ""identified two non-coding mutations in CDKN2A that showed near complete association with the phenotype. In addition, two missense mutations were identified at highly conserved sites, V9D [allele B1] and R10C [allele B2], and every bird tested with a confirmed Sex-linked barring phenotype carried one of these missense mutations."" These authors also identified a third allele (B0) ""identical to B1 and B2 for the entire 12 kb IBD region except that it has neither the V9D nor the R10C missense mutation"".
Schwochow Thalmann et al. (2017) showed ""that Sex-linked barring is genetically heterogeneous, and that the [four] mutations [reported by Hellström et al., 2010] form three functionally different variant alleles. The B0 allele carries only the two non-coding changes and is associated with the most dilute barring pattern, whereas the B1 and B2 alleles carry both the two non-coding changes and one each of the two missense mutations causing the Sex-linked barring and Sex-linked dilution phenotypes, respectively. The data are consistent with evolution of alleles where the non-coding changes occurred first followed by the two missense mutations that resulted in a phenotype more appealing to humans."" These also also report ""that one or both of the non-coding changes are cis-regulatory mutations causing a higher CDKN2A expression, whereas the missense mutations reduce the ability of [the CDKN2A-encoded alternate reading frame protein] ARF to interact with [Mouse double minute 2 homolog] MDM2.""" 9031
OMIA:000142 "The refined location determined by Wang et al. (2013) contains four positional candidate genes. Only one of these, SLCO1B3, is expressed in the shell gland of the uterus of blue-shelled hens but not in non-blue-shelled hens. Sequencing revealed the causal mutation to be ""a ~4.2 kb [retroviral] EAV-HP insertion in the 5′ flanking region of SLCO1B3"" (Wang et al., 2013). A genotyping survey of 38 chickens from two other breeds in which blue-eggshell segregates (Lushi and Araucana, the latter from North America) showed complete correlation of the presence/absence of the insertion mutation with blue-eggshell genotype. Eight other breeds in which blue eggshells do not appear were homozygous for the absence of the insertion mutation. Interestingly, the site of the insertion in the Araucana breed is 23bp upstream of the (identical) insertion site for the two Chinese breeds (Dongxiang and Lushi), indicating that the Chinese and American mutations arose independently (Wang et al., 2013).
Later in the same year, Wragg et al. (2013) reported the same insertion mutation in native chickens of Chile (Mapuche fowl) and in European derivative breeds. Consistent with the Araucana breed having arisen from the Chilean Mapuche fowl, the insertion in these chickens is at the same location as reported by Wang et al. (2013) for the Araucana breed. Wragg et al. (2013) also confirmed the different site of insertion in Chinese breeds, thus confirming the independent occurrence of the insertion in native Chinese and native Chilean chickens. As noted by Wragg et al. (2013), the fact that all European breeds with blue eggshells have the Mapuche insertion site rather than the Chinese insertion site suggests ""that the presence of blue eggs in Mapuche fowl, modern European and American breeds, did not involve birds from Asia"". As also noted by Wragg et al. (2013), the fact that the insertion is not present in any of the jungle fowl species from which domestic chickens arose, and the near-identity of sequence of the Chinese and Chilean insertions, suggest that the insertions are recent, post-domestication events." "Wang et al. (2010) mapped this trait to a region from 67.3–69.1 Mb on chromosome GGA1 in the Dongxiang chicken breed. Wragg et al. (2012) refined the location in the native Chilean Mapuche fowl (the original source of the Araucana breed of North America and Europe) and in derivative European breeds to ""two small regions (Gga 1:67.25–67.28 Mb, Gga 1:67.28–67.32 Mb) totalling ~75 Kb"". Using linkage analysis in the candidate region on data from 146 F2 hens from a cross between homozygous blue and homozygous non-blue birds of the Dongxiang breed, Wang et al. (2013) refined the location to ""a ~120 kb region from 67296991 bp to 67416784 bp on chromosome 1 on the UCSC chicken genome (May 2006 assembly)""." 9031
OMIA:000593 "In a conference abstract, Tammen et al. (2002) reported an undisclosed causative mutation in the comparative candidate gene SLC39A4. Yuzbasiyan-Gurkan and Bartlett (2006) reported the molecular basis of this disorder to be a splice-site variant within the SLC39A4 gene. ""The mutation leads to exon skipping, leaving the coding region in frame. The gene product is predicted to lack two critical motifs, which lie in adjacent transmembrane domains implicated in the formation of a pore responsible for the transport of zinc. While further functional studies are warranted, this unique variant is likely to be responsible for the impaired zinc absorption in this disease.""" 9913
OMIA:000881 Menotti-Raymond et al. (2010) provided convincing evidence that this form of retinopathy, so long studied, is the result of a frameshift mutation due to a single base deletion in the cone-rod homeobox-containing gene (CRX). 9685
OMIA:001541 "Building on their 2009 mapping results, Buitkamp et al. (2011) showed that this disorder in Simmental cattle is due to a 2-bp deletion in the MOCS1 gene. This gene encodes two peptides (MOCS1A and MOCS1B) via consecutive open reading frames. These two peptides are involved in the synthesis of molybdenum cofactor (Moco), which is involved in the synthesis of sulphite oxidase, the gene for which (SUOX) is the site of the mutation for the same disorder in Brown Swiss cattle (Drögemüller et al., 2010) (see OMIA 000059-9913). Thus we have an excellent example of mutations in two genes involved in the same biochemical pathway giving rise to the same biochemical deficiency and hence the same clinical signs. This is the first example of this type of genetic heterogeneity to be documented in cattle. As stated by Buitkamp et al. (2011), arachnomelia is thus the first example in cattle of an oligogenic disorder. (With thanks to Johannes Buitkamp)
In a project involving the whole-genome sequencing (WGS) of 43 Fleckvieh cattle with average coverage 7.46X (range 4.17X to 24.98X), Jansen et al. (2013) identified the same 2bp deletion in a known carrier.
Using a ""network-based disease gene prioritization approach"", Jiao et al. (2013) independently confirmed the same mutation in Simmental cattle." Buitkamp et al. (2009) mapped this disorder in Simmental cattle to chromosome BTA23. In stark contrast, Drögemüller et al. (2009) mapped the same disorder in Brown-Swiss cattle to chromosome BTA5 (see OMIA 00059). These results suggest the strong possibility of genetic heterogeneity for this disorder in cattle. (With thanks to Johannes Buitkamp). Interestingly, Seichter et al. (2011) mapped this disorder in Fleckvieh cattle to the same region of BTA23 as in Simmental, suggesting that the Fleckvieh mutation may be the same as the Simmental mutation. 9913
OMIA:001608 9615
OMIA:001759 "Sequencing of the only two candidate genes in the region of chromosome FCA E1 to which the disorder had been mapped (see Mapping section above) revealed a causative mutation in the WNK4 gene as ""(c.2899C.T) [which] causes a premature stop codon (CAG.TAG)"" (Gandolfi et al., 2012). This mutation leads ""to a truncated protein that lacks the C-terminal coiled-coil domain and the highly conserved Akt1/SGK phosphorylation site"" (Gandolfi et al., 2012)" A genome-wide association study (GWAS) using the illumina Infinium Feline 63K iSelect DNA array (62,897 SNPs) on 35 affected and 25 normal Burmese cats enabled Gandolfi et al. (2012) to map the disorder to a region in the vicinity of 72-73 Mb on chromosome FCA E1. 9685
OMIA:001529 "By comparing whole-genome sequence of a small number of Holsteins having the trait, with sequence data from hundreds of control animals, Capitan et al. (2014) confirmed the mapping results of Lawlor et al. (2014) and identified the causal mutation as BTA3 g.C9479761T, which corresponds to a missense mutation p.R160C in the COPA gene that encodes coatomer protein complex, subunit alpha.
By whole-genome sequencing of a Dominant Red heterozygote, Dorshorst et al. (2015) confirmed this causal mutation (c.478C>T; p.Arg160Cys). " "Dreger and Schmutz (2010) excluded linkage of this trait with polymorphisms in some of the common coat-colour genes, namely melanocortin 1 receptor (MC1R), agouti signalling protein (ASIP), attractin (ATRN) and melatonin receptor 1A (MTNR1A). However, linkage with microsatellites near, and SNPs within the 5' UTR of, another comparative candidate coat-colour gene (beta-defensin 103; DEFB103), located on chromosome BTA27, was detected.
Using SNP-chip genotypes of Holsteins from the shared national resource maintained by the Council on Dairy Cattle Breeding (CDCB; Reynoldsburg, Ohio), Lawlor et al. (2013) identified a haplotype at 8-12 Mb on chromosome BTA3 that co-segregates with this trait. While this results appears to contradict the earlier linkage result, it is known that there are many defensin genes/pseudogenes scattered throughout the bovine genome, and it is possible that the earlier results actually involved a defensin-like sequence on BTA3.
Dorshorst et al. (2015) used linkage mapping and GWAS to confirm that latter map location." 9913
OMIA:001593 By sequencing a strong positional candidate gene, namely TWIST1, Capitan et al. (2011) identified a small duplication (c.148_157dup (p.A56RfsX87)) that inactivates the gene. This frameshift mutation segregates perfectly with type 2 scurs. Capitan et al. (2011) mapped this trait in Charolais cattle to a 1.7Mb region of chromosome BTA4. 9913
OMIA:001508 "Based on the close histopathological resemblance to human MTM1 (see link to MIM entry above), Beggs et al. (2010) sequenced all 15 exons of the comparative candidate MTM1 gene in two affected male Labrador Retrievers, one obligate female carrier Labrador Retriever, and several non-affected dogs from other breeds. A potentially causative missense mutation (c.465C>A; p.N155K) in exon 7 was confirmed by further sequencing (""seven affected males, representing each of the affected families, were found to be hemizygous for this change, whereas three obligate female carriers were all heterozygous"") and genotyping (the mutation ""was not seen in any of 237 unrelated and unaffected Labrador Retrievers from throughout North America, Europe, and Australia, nor was it detected in any of 59 additional control dogs from 25 other breeds"").
Shelton et al. (2015) sequenced the same gene in a group of Australian Rottweilers segregating in a similar (X-linked) manner for very similar clinical signs, and discovered a different causal missense mutation (c.1151A>C; p.Q384P) in exon 11. Subsequent genotyping of this mutation in UK Rottweilers and other (unrelated) Australian Rottweliers showed no trace of the mutation, suggesting that this mutation is fairly new." 9615
OMIA:000386 "Sequencing of the comparative positional candidate gene BMP15 by Galloway et al. (2000) revealed ""A distinct single T→A transition occurs in FecXI carriers at nucleotide position 92 of the mature peptide . . . The mutation substitutes valine (V) with aspartic acid (D) at residue 31 (residue 299 of unprocessed protein) . . . The FecXI mutation is a non-conservative change in a highly conserved region of the protein.""" "Knowing that this gene is X-linked (see Inheritance section above), Galloway et al. (2000) used X-linked markers to map the gene to a region of chromosome OVAX orthologous with human Xp11.2–11.4. In this region lies the BMP15 gene ""encoding bone morphogenetic protein 15 (also known as growth differentiation factor 9B (GDF9B)) . . . [which] is a member of the transforming growth factor β (TGFβ) superfamily and is specifically expressed in oocytes, [but] its function is unknown"". Thus BMP15 became a likely positional candidate gene. The same authors then mapped the sheep BMP15 gene to the same region of OVAX, with zero recombination to FecX(I), providing very strong support for BMP15 being the FecX(I) gene." 9940
OMIA:001886 The most likely functional candidate gene in the region mapped by Kyöstilä et al. (2013) (see above) was ITAG10, encoding integrin subunit alpha 10. Sequencing all exons in this gene in two affecteds, an obligate carrier and a half-sib of an affected dog, revealed four exonic SNVs, namely three synonymous and one nonsense (c.2083C>T in exon 16; p.Arg695*). Widespread genotyping of the latter in families of Norwegian Elkhounds and Karelian bear dog, each segregating this disorder, indicated it to be the causal mutation. By conducting a GWAS on nine affected and nine control Norwegian Elkhounds, each genotyped with the Illumina CanineSNP20 SNP Chip (yielding 14,626 informative SNPs), Kyöstilä et al. (2013) mapped the disorder to a 2Mb region (from 60 to 62 Mb (CanFam2.0 assembly)) of chromosome CFA17, containing 33 genes. 9615
OMIA:000821 "By sequencing the most likely comparative candidate gene (based on clinical signs), Goldstein et al (2009) identified a causal mutation as a ""point mutation, G to A, . . . at the 3# splice acceptor site of intron 4"". They speculated ""that the lack of the necessary terminal AG sequence of intron 4 would result in a misplicing event. This would result in the splicing out of exon 5, resulting in a shortened and abnormal mRNA and protein.""" 9685
OMIA:001522 The causative mutation is an insertion of a guanine residue in exon 1 in the COL3 domain of COL9A3, causing an amino acid codon frameshift and a premature stop codon. Reduced RNA expression is found in affected retinas (Goldstein et al., 2010). It is currently thought that the causative mutation leads to collagen absence or deficiency in cartilage and ocular collagen, with a larger effect in vitreous and retinal tissue than in the limbs (Goldstein et al., 2010). CFA24 9615
OMIA:001322 Nadeau et al. (2007) showed that this plumage mutant corresponds to a SNP (giving rise to Phe282Ser) in the gene for TYRP1 - orthologous to the classic brown coat-colour locus in mammals. 93934
OMIA:001175 "By sequencing the candidate gene for this disorder (uroporphyrinogen III synthase; UROS), Clavero et al. (2010) identified two mutations for which a single affected cat was homozygous: ""c.140C>T (p.S47F) in exon 3 and c.331G>A (p.G111S) in exon 6"". The synergistic interaction of the two mutations caused feline CEP in the reported case (Clavero et al., 2010), a single cat having CEP, based on clinical and biochemical criteria. " 9685
OMIA:001904 "Adopting a comparative-candidate-gene strategy, based on a mutation in the gene EDNRB2 being causal for a similar phenotype (panda) in Japanese quail (OMIA 000375-93934), and on the appearance of an F1 hybrid between a panda (s/s) quail and a mo^w/mo^w chicken, Kinoshita et al. (2014) identified ""a non-synonymous G1008T substitution, which causes Cys244Phe amino acid substitution in exon 5 (which is part of the extracellular loop between the putative fourth and fifth transmembrane domains of EDNRB2) in the mutant [mo^w] chicken. This Cys244Phe mutation was also present in individuals of four Japanese breeds with white plumage. We also identified a non-synonymous substitution [G1272A] leading to Arg332His substitution that was responsible for the mottled (mo/mo) plumage phenotype.""" 9031
OMIA:000299 "Carneiro et al. (2017) showed ""that the dwarf allele constitutes a ~12.1 kb deletion overlapping the promoter region and first three exons of the HMGA2 gene leading to inactivation of this gene."" Very interestingly, mutation in this same gene is associated with body-size variation in dogs (OMIA 001968-9615) and horses (OMIA 001968-9796), and with beak size in Darwin's finches (OMIA 001992-48881); see the hyperlink to HMGA2 under the heading ""OMIA gene details page"" in the table below." Castle and Sawin (1941) showed that the dw gene is linked to agouti (OMIA 000201-9986) in linkage group IV. 9986
OMIA:001406 "Cameron et al. (2007): c.754C>T; p.Q252* in Clumber spaniels and Sussex spaniels
" CFA (29) 9615
OMIA:002040 Charlier et al. (2016): frameshift p.Leu1227Alafs∗134 9913
OMIA:002097 "Forman et al. (2015) identified an expanded GAA-repeat in intron 35 of the ITPR1 gene in affected dogs. The wildtype sequence contains 8 GAA repeats. The expanded disease-associated alleles carry an estimated 318-651 GAA repeats. Using immunohistochemistry Forman et al. (2015) observed reduced ITPR1 protein expression in Purkinje cells of the cerebellum and a distortion of the monoplanar orientation of the dendritic trees. ""This is the first reported naturally occurring pathogenic intronic repeat expansion in a nonhuman species."" (Forman et al. 2015)." Forman et al. (2015) genotyped microsatellite markers in 6 cases and 6 controls and detected homzygosity in the cases for two markers on chomosome 20. An extended linkage analyses using 13 cases and 47 controls gave a LOD score of 4.41 for the marker C20.374 on chromosome 20. Fine mapping defined a critical interval at chr20:15,601,140–17,116,778 based on the genomic coordinates of the CanFam2 assembly. 9615
OMIA:001716 By cloning and sequencing a very likely comparative candidate gene (based on a related human disorder), Tajima et al., 1999 reported that this disorder in Holsteins is due to a missense mutation (G254A) in the gene for dermatan sulfate proteoglycan, resulting in a serine-to-asparagine substitution in the serine-glycine repeat portion of the peptide, which is the binding portion of the peptide. The peptide is now called epiphycan, and its gene is called EPYC. It turns out that the related human disorder (Ehlers-Danlos syndrome, progeroid form) is due to mutations in a different gene (B4GALT7). 5q21 9913
OMIA:001244 "Menotti-Raymond et al. (2007) reported a causal mutation: ""A single-nucleotide polymorphism was characterized in intron 50 of CEP290 (IVS50 + 9T>G) that creates a strong canonical splice donor site, resulting in a 4-bp insertion and frameshift in the mRNA transcript, with subsequent introduction of a stop codon and premature truncation of the protein.""" 9685
OMIA:001685 "Nonneman et al. (2012) reported a GWAS in a pedigree of USMARC pigs segregating for a novel stress syndrome. The scan implicated just one region, namely chromosome ""SSCX at 25.1-27.7 Mb over the dystrophin gene (DMD)"". A missense mutation (R1958W) in exon 41 of the dystrophin gene appears to be the causative mutation." 9825
OMIA:000899 "Suzuki et al. (2012) used homologous recombination to create a disrupted allele of the IL2RG gene in somatic cells, followed by serial nuclear transfer, to establish a line of pigs segregating for the X-linked disrupted allele and hence for X-linked SCID.
Watanabe et al. (2013) produced a similar line of pigs by using a similar strategy, except that the gene disruption was created via zinc finger nuclease (ZFN) technology." 9825
OMIA:001112 The causative mutation in the Samoyed is a G to T substitution in exon 35 of COL4A5, which generates a premature stop codon (Zheng et al., 1994). The causative mutation in the Navasota mixed breed model is a 10 base pair deletion in exon 9 of COL4A5, which generates a premature stop codon. In the Navasota model, the mutant genotype at this locus has no apparent effect on X inactivation in females (Bell et al., 2008). CFX 9615
OMIA:001521 9615
OMIA:001676 "A causative mutation for this disorder was identified via a comparative positional cloning approach. First, as described in the Mapping section, a genome scan showed that the disorder locus is in a region of chromosome CFA29. The homologous region of the human genome (HSA8q21-22) contains the gene for cyclic nucleotide-gated channel β-subunit (CNBG3), mutations in which cause a very similar disorder in humans (see the OMIM entry above). Sequencing of this strong comparative positional candidate gene enabled the same authors to report that this disorder in German Short-hair Pointers is due to a ""missense mutation in exon 6 (D262N, nucleotide 784) within a conserved region of"" the CNGB3 gene, which encodes cyclic nucleotide-gated channel beta-subunit." Sidjanin et al. (2002) conducted a genome scan with microsatellites, and identified one microsatellite on CFA29, namely C29.002, completely linked to the disorder locus, with recombination fraction = 0 at a LOD score of 24.68. 9615
OMIA:001885 "The candidate region identified by Drouilhet et al. (2013) contains three genes. Sequencing revealed two single nucleotide variants (SNVs) that segregated with the FecL mutation, one (g.36938224T>A) in intron 7 of the gene B4GALNT2 (encoding beta-1,4-N-acetyl-galactosaminyl transferase 2) and the other (g.37034573A>G) 96 kb away in an intergenic region. Expression analyses indicated ""overexpression of B4GALNT2 in the ovary leading to atypical glycosylation of inhibin, an important hormone regulating ovarian function""; either or both (or neither) of the two SNVs could be causal. Importantly, the authors concluded ""For the first time a fecundity gene in sheep does not belong to the TGFß/BMP signaling genes and it opens new fields of investigation regarding ovarian glycosylation and the pathogenesis of fertility disorders in women.""" "A genome scan with 89 microsatellites genotyped on nine half-sib families segregating at the FecL locus, conducted by Drouilhet et al. (2009), mapped the FecL locus to chromosome OAR11. Subsequent fine mapping with additional OAR11 markers ""refined the location of the FecL locus to an interval of 2.1 centiMorgan (cM) between markers DLX3 and BM17132"". Additional fine mapping narrowed the interval to a region showing conserved synteny with a region on human chromosome HSA17 spanning 1.1Mb and containing 20 genes.
Further fine mapping and sequencing enabled Drouilhet et al. (2013) to narrow the candidate region to 197kb." 9940
OMIA:000515 "By sequencing a positional candidate gene in the BIO14.6 strain, Nigro et al. (1997) identified a causal mutation in this strain and in the TO-2 strain (see OMIA 000162-10036) as being a large deletion in the delta-SG gene. Later that same year, Sakamoto et al. (1997) identified what appears to be the same causal mutation: ""A breakpoint causing genomic deletion was found to be located at 6.1 kb 5′ upstream of the second exon of δ-SG gene, and its 5′ upstream region of more than 27.4 kb, including the authentic first exon of δ-SG gene, was deleted. This deletion included the major transcription initiation site, resulting in a deficiency of δ-SG transcripts with the consequent loss of δ-SG protein in all the CM hamsters""." 10036
OMIA:000679 Matsumoto et al. (2008) provided strong evidence implicating a missense mutation in the gene for ubiquitin ligase (WWP1) as the cause of this disorder. Yoshizawa et al. (2003) excluded three possible candidates (SNTB1, SDC2 and GEM) for this locus on GGA2q. 9031
OMIA:001960 Missense mutatiopn: c.949T>C, p.W317R (11,131,497 bp; rs110793536; UMD3.1 assembly) in SUGT1 (Pausch et al., 2015) Chromosome BTA12: 10,859,759-12,805,107 (UMD3.1 genome assembly) (Pausch et al., 2015) 9913
OMIA:000889 Wells et al. (2012) reported a nonsense mutation (c.535A>T; p.R179X) in the FGF20 gene as the cause of this trait. In a novel (for non-humans) strategy of genotyping just two pools of DNA (from 86 homozygotes and from 120 heterozygotes) with the Illumina 60 K chicken SNP chip, Wells et al. (2012) mapped this trait to a 1.25 Mb region of chromosome 4. 9031
OMIA:000384 Adopting a candidate-gene approach, Hanrahan et al. (2004) showed increased fecundity in heterozygotes and sterility in homozygotes associated with a 718C>T base substitution in the X-linked BMP15 gene and with a 1184C>T base substitution in the autosomal GDF9 gene, resulting in amino-acid substitutions Q239X and S395F, respectively. The former mutation is now called FecX(G) and the latter FecG(H). 9940
OMIA:001722 "Using targeted DNA capture and massively parallel resequencing of the 1.2 Mb region that contained 24 genes, Testoni et al. (2012) identified a causal mutation as a ""KDM2B missense mutation (c.2503G>A) leading to an amino acid exchange (p.D835N) in an evolutionary strongly conserved domain"". As the same authors report, ""The KDM2B gene (also known as JHDM1B and FBXL10) encodes a histone H3 lysine 36 dimethyl (H3K36me2)-specific demethylase . . . Histone methylation is one important transcription regulatory system that affects mammalian development and cell differentiation""." "Testoni et al. (2012) ""localized the causative mutation to a 1.2 Mb interval on BTA 17 by genome-wide association and identical by descent mapping"". " 9913
OMIA:000543 "By adopting a comparative positional cloning approach, involving a linkage analysis as described in the Mapping section, Casal et al. (2005) discovered that the causative mutation of XHED in the colony of dogs described by Casal et al. (1997) is a ""nucleotide substitution (G to A) in the splice acceptor site of intron 8 . . . In the presence of the A residue, a cryptic acceptor site within exon 9 is used, leading to a frame shift and use of a premature stop codon that truncates the translation of both isoforms, EDA-A1 and EDA-A2, resulting in the absence of the TNF-like homology domain, the receptor-binding site of ectodysplasin."" Using the genetic variant nomenclature of 2015, the causative variant can be described as c.910-1G>A.
In each of three affected mixed-breed dogs (two of which were brothers) from Israel, Waluk et al. (2016) reported that ""the whole genome sequence data did not reveal any non-synonymous EDA variant in the affected dogs""but ""the EDA transcript in the affected dogs lacked 103 nucleotides encoded by exon 2. We speculate that this exon skipping is caused by a genetic variant located in one of the large introns flanking this exon, which was missed by whole genome sequencing with the illumina short read technology. The altered EDA transcript splicing most likely causes the observed ectodermal dysplasia in the affected dogs. . . . The variant designation for this frame-shifting exon skipping on the transcript level is r.385_487del. The predicted variant on the protein level is p.Met129Valfs*112 and the predicted mutant protein lacks the functionally important collagen-like and TNF-signaling domains""." A linkage analysis with 5 markers evenly spaced along the length of the X chromosome enabled Casal et al. (2005) to show that the XHED locus is located near the centromere, very near to one of the two comparative candidate genes, namely EDA (ectodysplasin). 9615
OMIA:001602 93934
OMIA:002101 "As reported by Hollman et al. (2017), via a personal communication from Dr Jon Beever, ""An amino acid exchange in the Ras-related Protein Rab-38 (RAB38) gene was identified as the disease causing mutation"". A 2015 press release from the American Simmental Association (Anon., 2015) reported ""Recently Dr. Beever has found the causative mutation and developed a diagnostic test for OH."" It appears that the mutation arose originally in Angus cattle (Anon., 2015; https://www.angus.org/pub/OH/OHInfo.aspx)." 9913
OMIA:001542 Zhao et al. (2011) reported this disorder in Corriedale sheep as being due to a nonsense mutation in exon 6 of the DMP1 gene. Using the ovine SNP50 BeadChip, Zhao et al. (2011) mapped this disorder to a 6Mb region of chromosome OAR6. 9940
OMIA:001512 V595E in canine BRAF, which is homologous to V600E in human BRAF (Decker et al., 2015) Position 8296284 on chromosome CFA16 (Decker et al., 2015) 9615
OMIA:002034 "Fenn et al. (2016): ""an exon 26 splice donor variant (CanFam3.1, chr12:45,530,566, c.2653 + 1G > A) in the Sorting Nexin 14 (SNX14) gene""" 9615
OMIA:001314 "By mapping, cloning and sequencing a very likely comparative candidate gene (based on information concerning closely related genes associated with similar disorders in humans and dogs), Petersen-Jones et al. (1999) showed that the molecular basis of this particular type of progressive retinal atrophy is the deletion of a single base in codon 616 of the gene for the alpha subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE6A), which is ""predicted to lead to a frame shift resulting in a string of 28 altered codons followed by a premature stop codon""." The first step in the investigation of Petersen-Jones et al. (1999) was to show that the canine PDE6A gene co-segregates with the disorder. 9615
OMIA:001686 "Sartelet et al. (2012) identified the causative mutation as a ""c124-2A>G splice variant in intron 1 of the RNF11 gene"". This gene encodes RING finger protein 11, which is a key regulator in the A20 complex of the inflammatory response." 9913
OMIA:000206 "Adopting a comparative candidate gene strategy, Fontanesi et al. (2014) sequenced the rabbit MLPH gene and identified a causal mutation for the recessive dilute allele as ""a deletion of one nucleotide in exon 5 (g.549853delG) that causes a shift in the reading frame that determines a completely different protein from the beginning of this exon . . . until the second half of exon 8 in which a stop codon would be introduced"".
By sequencing the MLPH gene in two dilute and one black rabbits, Lehner et al. (2013) discovered a ""c.111-5C>A splice acceptor mutation within the polypyrimidine tract of intron 2"", resulting in ""p.QGL[37-39]QWA and a premature stop codon at p.K40*"" as being a causal mutation for dilute. They also reported another causal mutation, namely a ""frame shift mutation within exon 6 (c.585delG)"", which is actually the same as the mutation reported by Fontanesi et al. (2014). " 9986
OMIA:002039 Charlier et al. (2016): deletion p.Lys1730del 9913
OMIA:000001 "Adams et al. (2012) revealed the causal mutation of HH1 as ""a nonsense mutation in APAF1 . . . , which is predicted to truncate approximately one-third of the encoded APAF1 protein"". Because functional APAF1 peptide is required for embryo development, homozygosity for this allele results in natural spontaneous abortion, and, consequently, perceived reduced fertility in carrier bulls that happen to be mated to carrier cows.
Adams et al. (2016) published the causal mutation as being ""a nonsense mutation in APAF1 (apoptotic protease activating factor 1; APAF1 p.Q579X) within HH1 using whole-genome resequencing of Chief and 3 of his sons. This mutation is predicted to truncate 670 AA (53.7%) of the encoded APAF1 protein that contains a WD40 domain critical to protein–protein interactions.""" 9913
OMIA:000319 "Of the 23 genes in the mapped region (see above), Gandolfi et al. (2016) identified the most likely candidate as TPRV4. mutations in which are ""responsible for a spectrum of dominantly inherited human skeletal dysplasias"" (see Possible human homologues above). Sequencing of the coding sequence of this gene in 2 affecteds and 3 controls, followed by direct sequencing in other cats revealed just one missense mutation (c.1024G>T; p.V342F) as the likely cause: ""all 21 Scottish shorthair cats were homozygous for the wild-type allele, two Scottish fold cats were homozygous for the variant allele and 39 Scottish fold cats were heterozygous. A single Scottish fold cat tested homozygous wild-type"". Further ""Screening of 648 cats representing several breeds and domestic shorthair cats of unknown ear type demonstrated the c.1024G>T substitution was detected only in the Scottish fold breed and was absent in all other populations.""" "By conducting a case-control GWAS on ""35 Scottish fold and 32 controls (17 Scottish Shorthair, 8 Selkirk Rex, 3 British Shorthair and 4 Persian)"", each genotyped with the Illumina Infinium Feline 63K iSelect DNA chip (yielding 46,203 informative SNPs), Gandolfi et al. (2016) mapped this disorder to a region of chromosome FCAD3 from D3:24,380,099 bp to D3:25,202,262 bp. " 9685
OMIA:000374 57661
OMIA:001939 " Using genotype data from tens of thousands of North American Holsteins, Jerseys and Brown Swiss cattle each genotyped with approximately 50K SNPs on the BovineSNP50 BeadChip, VanRaden et al. (2011) identified five new potential recessive lethal haplotypes by searching for common haplotypes that are never homozygous in live animals. One of these haplotypes (424.49) was roughly mapped to the region 7-16Mb on chromosome BTA19), but was not pursued further, by VanRaden et al. (2011). A subsequent study of another 2,959 Brown Swiss from Austria and Germany enabled Schwarzenbacher et al. (2012) to confirm the existence of this lethal haplotype and to refine its location to a region 10.140-11.049Mb on BTA19. However, its effect was still not clear: these authors noted that this haplotype ""is suspect and needs further research"". FN thanks Cole et al. (2014) for alerting him to the latter results.
In a preprint posted on the Cold Spring Harbor bioRxiv preprint server on 1st March 2016, Schwarzenbacher et al. (2016) documented the quite marked effects of this haplotype on mortality, and reported the discovery of its causal mutation as ""a missense mutation in TUBD1 (rs383232842[T>C], p.H210R)"". This is the first result from a preprint to be included in OMIA. A refereed version of this paper was published three months later in BMC Genomics (see reference list)." 9913
OMIA:002089 "By whole-genome sequencing a single SAMS affected Russell group terrier (RGT) dog, and comparing that sequence with whole-genome sequence from 81 canid reference genomes, Gilliam et al. (2014) identified 23 missense variants that were homozygous in the affected dog. Of the two variants that occurred in comparative candidate genes, one (KCNJ10:c.627C>G; p.Ile209Met) was shown by subsequent sequencing and genotyping of other dogs to be causal for this subtype of ataxia, namely ""spinocerebellar ataxia with myokymia, seizures, or both (SAMS)"". Rohdin et al (2015) confirmed these findings and noted that the KCNJ10:c.627C>G (p.Ile209Met) variant also segregates in Smooth-Haired Fox Terriers and related breeds. Gast et al. (2016) confirmed that the KCNJ10 c.627C>G (p.Ile209Met) variant accounts for most (but not all) cases in another cohort of Parson Russell Terriers and in Jack Russell Terriers.
A likely causal variant in Malinois dogs with spongy degeneration with cerebellar ataxia 1 (SDCA1), namely a missense mutation in KCNJ10: c.986T>C; p.Leu329Pro, was reported by a Belgian/UK team (Stee et al., 2016; Van Poucke et al., 2017, accepted for publication 29 September 2016). The phenotype in SDCA1 affected Malinois dogs is slightly different from the phenotype in the terriers with SAMS. Mauri et al. (2017; accepted for publication 16 December 2016) reported the same likely causal mutation in this breed." Mauri et al. (2017) investigated six litters of Malinois dogs with ataxic puppies by linkage analysis. This analysis revealed heterogeneity in the material. Four of the six litters had overlapping linkage signals. The authors additionally performed a homozygosity mapping analysis, for which they used six affected puppies from the four families and one additional unrelated case. The combined linkage and homozygosity analysis resulted in a ~1.4 Mb critical interval on chromosome 38 (chr38:21,060,597-22,475,242; CanFam 3.1 assembly). 9615
OMIA:001719 9940
OMIA:001493 "By sequencing the two obvious comparative candidate genes (UROS and HMBS) in affected cats from four unrelated populations, Clavero et al. (2010) identified four different causative mutations in HMBS (one in each population):
1.a 3 bp deletion in exon 14 (c.842_844delGAG)
2.a T duplication in exon 5 causing a frameshift and protein truncation (c.189dupT)
3.a C to T transition in exon 9 (c.445C>T; p.R149W)
4.a G to A transition in exon 6 (c.250G>A; p.A84T) (autosomal recessive, most likely because the mutant allele encodes ""a stable enzyme with ∼35% of wild-type activity"" (compared with mutations 2 and 3 above, which encode ""mutant enzymes with <1% wild-type activity"".
Two new HMBS mutations were identified by Clavero et al. (2013): ""one cat had a deletion (c.107_110delACAG) and one cat had a splicing alteration (c.826-1G>A), both leading to premature stop codons and truncated proteins (p.D36Vfs6 and p.L276Efs6, respectively).""
" 9685
OMIA:001965 "Menzi et al. (2016) ""resequenced the entire genomes of an affected calf and a healthy partially inbred male carrying one copy of the critical 2.24-Mb chromosome 11 segment [identified by Kipp et al., 2015] in its ancestral state and one copy of the same segment with the cholesterol deficiency mutation. [They] detected a single structural variant, homozygous in the affected case and heterozygous in the non-affected carrier male. The genetic makeup of this key animal provides extremely strong support for the causality of this mutation. The mutation represents a 1.3kb insertion of a transposable LTR element (ERV2-1) in the coding sequence of the APOB gene, which leads to truncated transcripts and aberrant splicing [p.Gly135ValfsX10)]. This finding was further supported by RNA sequencing of the liver transcriptome of an affected calf. ""
Charlier (2016) confirmed this result, but with a different estimate of the size of the insertion: ""the causative mutation corresponds to the sense insertion of a ~7kb full-length bos Taurus endogenous retroviral element (BoERV) in exon 5 of the Apolipoprotein B gene (APOB), resulting in complete transcriptional termination downstream to the insertion point.""
The 1.3kb insertion result was confirmed by Schütz et al. (2016), who reported that the causal mutation is ""a 1.3kbp insertion of an endogenous retrovirus (ERV2-1-LTR_BT) into exon 5 of the APOB gene at BTA11:77,959kb. The insertion is flanked by 6bp target site duplications as described for insertions mediated by retroviral integrases. A premature stop codon in the open reading frame of APOB is generated, resulting in a truncation of the protein to a length of only <140 amino acids"".
Gross et al. (2016) reported that the causal mutation affects ""lipid metabolism in affected [homozygous] Holstein calves and adult [heterozygous] breeding bulls. Besides cholesterol, the concentrations of PL, TAG, and lipoproteins also were distinctly reduced in homozygous and heterozygous carriers of the mutation. Beyond malabsorption of dietary lipids, deleterious effects of apolipoprotein B deficiency on hepatic lipid metabolism, steroid biosynthesis, and cell membrane function can be expected, which may result in unspecific symptoms of reduced fertility, growth, and health""." By conducting a GWAS on 23 affected and 11,177 normal German Holstein calves, each genotyped with the Illumina 54k SNP chip, Kipp et al. (2015) mapped this disorder to chromosome BTA11. Subsequent homozygosity mapping of this chromosome narrowed the candidate region down to a haplotype in the region of approximately 74.4 - 77.1 Mb. Interestingly, one of the human causal genes (APOB, for hypobetalipoproteinemia, familial, 1; OMIM 615558) maps very near to the causal cattle haplotype. 9913
OMIA:001415 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Credille et al. (2005) documented the molecular basis of this disorder in a family of Norfolk terrier dogs: ""Affected dogs were homozygous for a single base GT>TT change in the consensus donor splice site of intron 5 in [the gene for keratin 10] KRT10. . . . . The mutation caused activation of at least three cryptic or alternative splice sites. Use of the cryptic sites resulted in transcripts containing premature termination codons. One transcript could result in shortening of the proximal portion of the 2B domain before the stutter region.""" 9615
OMIA:002042 Charlier et al. (2016): nonsense (stop-gain) p.Arg64∗ 9913
OMIA:001516 9615
OMIA:001621 Martin et al. (2008) reported a deficiency of alpha-dystroglycan in affected cats but could find no causative mutation in the DAG1 gene that encodes this peptide. 9685
OMIA:001671 "Shinomiya et al. (2011) reported that the characteristic hyperpigmentation of Silky chickens is due to a 130kb duplication that contains five genes, including ""endothelin 3 (EDN3) which [encodes] a potent mitogen for melanoblasts/melanocytes"". The duplication of these genes results in substantial overexpression which gives rise to the hyperpigmentation. This discovery was extended by Dorshorst et al. (2011), who showed that the FM mutation actually involves ""the duplication of two genomic regions, each larger than 100 kb and separated by 417 kb on wild-type [GGA20] chromosomes"". Their analysis of a range of breeds strongly suggested that the mutation giving rise to this double duplication is the cause of FM in all breeds of chickens, and hence is an old mutation, predating the divergence of breeds." "Dorshorst et al. (2010) were the first to map this locus, reporting its location as ""10.3–13.1 Mb on chromosome [GGA]20"". This mapping was slightly narrowed by Shinomiya et al. (2011) to ""10.2-11.7 Mb of chicken chromosome [GGA]20""." 9031
OMIA:001033 "Sequencing and expression analysis of one of the four positional candidate genes (see Mapping section) by Bannasch et al. (2008) identified the causal mutation as ""a missense mutation (G616T;C188F)"" in the SLC2A9 gene. All Dalmations are homozygous for this mutation." "Linkage mapping followed by positional cloning by Bannasch et al. (2008) localised this disorder to a 2.5Mb region on chromosome CFA3. Homozygosity mapping reduced the region to 333kb, containg just four genes.
By conducting a proof-of-principle across-breed GWAS on ""10 total affected dogs from three breeds and 59 controls from 25 breeds"", each genotyped with the Affymetrix Version 2 Custom Canine SNP (comprising 49,663 SNPs), Bannasch et al. (2010) confirmed the location of the causal gene on chromosome CFA3 first reported by Bannasch et al. (2008). " 9615
OMIA:000595 "Bauer et al. (2017): ""a 24 bp deletion at the exon 2 to intron 2 boundary (c.46_58 + 11del), predicting premature translational termination due to abnormal splicing of exon 1 to exon 3 or 4""" 9685
OMIA:001718 "Following a comparative positional candidate gene approach (described above in the Mapping section), Nielsen et al. (2000) cloned and sequenced the porcine COL10A1 gene and identified a causative missense mutation, namely ""a single G to A transition in exon 3 that results in a Gly-to-Arg substitution, G590R, in the carboxyl terminus of the protein""." An initial genome scan with 70 microsatellite markers implicated chromosome SSC1. Mapping with additional SSC1 markers mapped the disorder to 8.3cM from marker Sw781. The authors noted that this region is homologous to human chromosome HSA6q21-22.3, which harbours the gene COL10A1, mutations in which cause Schmid metaphyseal chondrodysplasia, a disorder very similar to the pig disorder. Thus the authors had identified a comparative positional candidate gene. 9825
OMIA:001451 """A missense mutation (T809C) in exon 4, resulting in a L270P substitution in the third membrane-spanning domain of GlyT2"" (a glycine transporter). (Charlier et al., 2008). The GlyT2 gene is now called SLC6A5. Gill et al. (2012) reported the same mutation in Belgian Blues from the UK. " "In a pioneering use of tens of thousands of SNP markers (""using either the 25K Affymetrix SNP panel or a custom-made 60K Illumina panel""), Charlier et al. (2008) identified a single 3.61 Mb region on BTA29 in which 7 affected calves were significantly more homozygous for the same allele at each of many SNPs, when compared with 24 normal controls. An investigation of all 13 genes in that region identified the most likely culprit as being SLC6A5, which encodes a glycine transporter. " 9913
OMIA:001935 "Analysis of whole-genome sequence data in the candidate region (see Mapping section above), from one affected calf and 42 normal Fleckviehs enabled Jung et al. (2014) ""revealed a nonsense mutation (p.W215X) in a phospholipase encoding gene (PLD4) as candidate causal polymorphism"". The causality of this mutation was confirmed by sequencing for this mutation in ""3,650 animals representing three different breeds"". The complete description of the mutation is ""c.G645A, p.W215X, BTA 21:71,001,232 bp, rs378824791"". " "Having excluded (by sequencing) the SLC39A4 gene, mutations in which cause hereditary zinc deficiency in Holstein-Friesians (see OMIA 000593-9913), Jun et al. (2014) conducted a GWAS on 8 affected calves and 1,339 normal Fleckvieh bulls (each of which had been genotyped with the Illumina BovineHD BeadChip (yielding 644,450 informative SNPs), which mapped this disorder to chromosome BTA21, in ""an 18.19 Mb interval from 53,140,245 bp to 71,333,740 bp"". Subsequent ""Autozygosity mapping within the distal region of BTA 21 revealed a common 1,023 kb segment of extended homozygosity in the eight affected animals (70,550,045 bp – 71,573,501 bp)"". " 9913
OMIA:000245 Fine-mapping and subsequent sequencing within the candidate region on CFA27 (see Mapping section) enabled Cadieu et al. (2009) to identify the causal mutation as a missense SNP (Arg151Trp) in the KRT71 gene. By conducting a GWAS on 31 curly-hair and 41 wavy-hair Portugese Water dogs, each genotyped with an Affymetrix Version 2 Canine SNP chip (yielding 56,395 informative SNPs for analysis), Cadieu et al. (2009) highlighted a region on chromosome CFA27. 9615
OMIA:000110 9615
OMIA:001917 "Of the two genes in the candidate region (see mapping section), one (ARHGEF10) was a comparative candidate (see OMIM link above). Sequencing of this gene in affecteds and controls enabled Ekenstedt et al. 92014) to identify ""a 10 bp deletion in affected dogs that removes four nucleotides from the 3′-end of exon 17 and six nucleotides from the 5′-end of intron 17 (c.1955_1958+6delCACGGTGAGC). This eliminates the 3′-splice junction of exon 17, creates an alternate splice site immediately downstream in which the processed mRNA contains a frame shift, and generates a premature stop codon predicted to truncate approximately 50% of the protein. Homozygosity for the deletion was highly associated with the severe juvenile-onset PN phenotype in both Leonberger and Saint Bernard dogs"". " A GWAS on 52 affected and 41 control Leonbergers, each genotyped with the Illumina CanineHD BeadChip (yielding 101,284 informative SNPs) enabled Ekenstedt et al. (2014) to map this disorder to a region of chromosome CFA16, with the strongest association at 57,375,008 bp (CanFam2). Homozygosity mapping identified a 250kb region. 9615
OMIA:001216 Hadjiconstantouras et al. (2008) could not find any substantial association between polymorphisms at this locus and coat colour in Meishan x Large White cross. Lim et al. (2011) provided convincing evidence that whole-body roan is due to a U(26) repeat in intron 5 of the KIT gene, which is likely to mediate skipping of exon 5 of the gene in some tissues including skin, resulting in the roan phenotype. 9825
OMIA:001562 9913
OMIA:000649 Sequencing of the prime candidate gene PITX3 in affecteds and normals, by Becker et al. (2010), identified a missense mutation (338G>C, R113P) in a conserved region of the gene as being causative. Becker et al. (2010) used the first-generation ovine SNP50 BeadChip to map this disorder to a 2.4 Mb region of chromosome OAE22. This region contains the gene PITX3, mutations in which cause some forms of this disorder in humans. 9940
OMIA:001669 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Dekomien et al. (2000) reported the causal mutation in Sloughi dogs as being ""an 8-bp insertion after codon 816"" of the PDE6B gene." 9615
OMIA:001594 9615
OMIA:000809 "Using the comparative candidate gene strategy (based on the same clinical signs in humans being due to mutations in the JAK2 gene), Beurlet et al. (2011) sequenced exon 14 of the canine JAK2 gene in five affected dogs (a female ""crossbred"", a male Maltese, a female Poodle, a female Yorkshire, and a female ""Westie"") and discovered a possible causal triple-mutation variant (c.1849G>T, c.1852T>C, c.1853G>T; p.V617F, p.C618L) in just one dog (the ""crossbred""), the other four having only wild-type sequence. Evidence that this variant is likely to be causal was based on (a) This same variant (at the peptide level) is causal in humans; and (b) ""Transfection of BaF3 cells with the triple mutant cDNA, but not with the wild-type complementary DNA, resulted in cytokine-independent growth and constitutive signal transducer and activation of transcription 5 phosphorylation"". As the authors note, the fact that four of the five affected dogs do not have the likely causal variant indicates that ""we cannot exclude the presence of different mutations of JAK2 or mutations of proteins upstream or downstream of JAK2. . . . alternate mutations may be found in JAK-STAT regulating pathways, such as reported in the LNK gene [in humans]"". The fact that the five sequenced dogs are a cross between un-named breeds and one each of four different breeds, explains why the likely causal variant was seen in only one dog. Given the lack of knowledge of the breeds involved in the crossbred dog, and the lack of the likely causal variant in the other four dogs, it can be concluded that testing for this particular variant will not be particularly effective in any breed until further information is obtained on the distribution and effect of this variant. " 9615
OMIA:001890 Two independent papers published simultaneously in 2015 have shown that the two variant morphs (satellites and faeders) are associated with a 4.5Mb inversion on the ruff orthologue of chicken chromosome GGA11 which, due to the well-known lethality of recombinants within an inversion, has created a supergene determining male breeding behaviour, body size and plumage colour. The large sequence divergence between the wild-type and inverted variant (1.4%) indicates that the inversion happened about 4 million years ago. The inversion disrupts an essential gene (CENPN) and is therefore lethal in the homozygous condition, which means that it has been maintained as a balanced polymorphism for millions of years. Furthermore, some 500,000 years ago, the inverted supergene recombined with the wild-type allele creating a second version. Faeders possess one copy of the original inverted supergene, satellite males have one copy of the newer recombinant version, and independents lack either version. The inverted region contains about 90 genes, which include five genes (e.g. HSD17B2) affecting the metabolism of steroid hormones and the MC1R gene that is assumed to explain the white colour in satellites. (based on text kindly provided by Leif Andersson) 198806
OMIA:002016 "Hytönen et al. (2016) identified a likely causal mutation in Wire Fox Terriers as a ""c.865_866delTC variant [that] results in a frameshift and a premature stop codon, (p.S289Gfs*15), leading to a truncated protein in the first half of the coding region""." 9615
OMIA:001540 Sequencing of the six most-likely candidate genes in the CFA34 candidate region (see Mapping section) region identified a nonsense mutation in the CCDC39 gene, which encodes coiled-coil domain-containing protein 39. By searching for CCDC39 mutations in PCD cases in humans (where PCD is a heterogeneous inherited disorder), they were able to identify a new cause of human PCD. This study highlights the power of canine genomic studies to inform knowledge of human inherited disorders that are genetically heterogeneous. By conducting a GWAS on 5 affected and 15 control Old English Sheepdogs (that all traced back to a common ancestor), each genotyped with an Affymetrix v2.0 Canine SNP chip, Merveille et al. (2011), from the LUPA consortium, identified a 15Mb region of autozygosity on chromosome CFA34. 9615
OMIA:001806 "By sequencing the most likely candidate gene in the candidate region upstream from ASIP (see Mapping section above), Dreger et al. (2013) discovered that the black-and-tan/saddle tan polymorphism is due to ""a 16-bp duplication (g.1875_1890dupCCCCAGGTCAGAGTTT) in an intron of hnRNP associated with lethal yellow (RALY), which segregates with the black-and-tan phenotype in a group of 99 saddle tan and black-and-tan Basset Hounds and Pembroke Welsh Corgis. In these breeds, all dogs with the saddle tan phenotype had RALY genotypes of +/+ or +/dup, whereas dogs with the black-and-tan phenotype were homozygous for the duplication. The presence of an a y/_ fawn or e/e red genotype is epistatic to the +/_ saddle tan genotype. Genotypes from 10 wolves and 1 coyote indicated that the saddle tan (+) allele is the ancestral allele, suggesting that black-and-tan is a modification of saddle tan."" However, the authors also reported that ""An additional 95 dogs from breeds that never have the saddle tan phenotype have all three of the possible RALY genotypes"", indicating that there is more to this story than has been revealed to date." "Using genotype data from the Affymetrix Canine Array v2.0 100K SNP chip, Dreger et al. (2013) conducted a GWAS on ""130 black-and-tan and saddle tan cases and 596 non-pattern controls"" and another GWAS on ""33 saddle tan cases and 97 black-and-tan controls"". The first GWAS confirmed the ASIP locus on chromosome CFA24 as being responsible for the black-and-tan and saddle tan phenotypes (see OMIA 000201-9615). The second GWAS revealed that ""the saddle tan phenotype maps specifically to a region separate from and upstream of ASIP""." 9615
OMIA:001976 "In Basset Hounds, Oliver et al. (2015) reported a likely causal mutation: ""a 19 bp deletion in exon 2 that alters the reading frame and is predicted to lead to a truncated protein"" (CanFam3.1 chr3:40,614,853–40,614,872).
In Basset Fauve de Bretagne dogs, the same authors reported a likely causal mutation in the same gene: ""a missense mutation in exon 11 causing a glycine to serine amino acid substitution ([CanFam3.1 chr3:40,808,345; c.1552G>A]; G519S) in the disintegrin-like domain of ADAMTS17 which is predicted to alter protein function"". " 9615
OMIA:000369 "By cloning and sequencing a very likely comparative candidate gene (based the molecular cause of albinism on other species), Tobita-Teramoto et al. (2000) identified a ""six-nucleotide deletion (−ΔGACTGG) from 817 through 822 bp at codons 237 and 238"" of the chicken tyrosinase (TYR) gene as being causative. ""This mutation deletes two amino acids in the tyrosinase protein: 237, aspartic acid, and 238, tryptophan.""" 9031
OMIA:000810 "Polydactyly results from faults in the regulation of the developmental gene Sonic Hedgehog (SHH), which is expressed only at the border of the posterior limb bud, in a region called the zone of polarizing activity (ZPA). The faults in regulation result from mutations in an enhancer located in exon 5 of the LMBR1 gene, located about 1 MB upstream of SHH. The enhancer is called the ZPA regulatory sequence (ZRS). Thus polydactyly results from mutations in ZRS, which affect expression of SHH in the developing limb bud. The first report of the causal mutation (a SNP in the SHH enhancer) was by Dorshorst et al. (2010). This discovery was confirmed by Maas et al. (2011).
Zhang et al. (2016) showed that this mutation is causal in 24 indigenous Chinese breeds, but is not causal for Polydactyly in the Houdan breed, from France.
" "This disorder was originally mapped to linkage group E (Warren, 1949). Using bulked segregant analysis with microsatellite markers, Pitel et al. (2000) mapped it to chromosome GGA2p, a result confirmed by Yang et al. (2013). Dorshorst et al. (2010) refined the location to 4.8Mb on chromosome GGA2p. Using linkage analysis and GWAS in 367 members of an F2 of a cross between Beijing-You chickens and Cobb-Vantress commercial broilers, each genotyped with the Illumina 60K Chicken SNP Beadchip (yielding 42,585 informative SNPs), Sun et al. (2014) confirmed the SSH region on chromosome GGA2 as being the most important, but also obtained genome-wide significance for SNPs on chromosomes GGA20 and GGA26.
Sheng et al. (2015) reported the strongest association with Polydactyly in a region on chromosome GGA2 that contains the BRAM1 gene. This paper was withdrawn in March 2016 (Sheng et al., 2016).
Zhang et al. (2016) showed that the causal mutation for Polydactyly in European breeds maps to the same region of chromosome GGA2 as the mutation that is causal in Chinese breeds, but is not the same mutation." 9031
OMIA:001581 "Gandolfi et al. (2010) showed that the Devon rex mutation and the Sphynx hairless mutation (OMIA 001583-9685) are both due to mutations in the KRT71 gene which encodes keratin 71: ""An 81-bp deletion (c.1108-4_1184del), including the last 4 bp of intron 6 and the first 77 bp of exon 7, followed by a 8-bp insertion (c.1184_1185insAGTTGGAG) and a base insertion (c.1196insT), was found to be homozygous in the two Devon Rex cats""." 9685
OMIA:001880 "Using the direct candidate gene strategy, based on clinical signs, Brons et al. (2013) identified ""a single base missense mutation (c.964G>A) [in SLC7A9] changing the small hydrophobic glycine residue to the larger, charged basic amino acid arginine (p.Gly322Arg) in transmembrane domain 9 of the light subunit bo,+AT"" as causal in Miniature Pinschers. " 9615
OMIA:001085 "Building on the mapping results describe above in the Mapping section, Milan et al. (2000) constructed a 2.5 Mb contig of BAC clones covering the region in which RN resides, and used it to fine-map the RN locus. Sequencing of the most likely BAC clone revealed three putative coding sequences, one which showed some homology with genes encoding the gamma subunit of AMP-activated protein kinase (AMPK). Noting that AMPK ""has a key role in regulating energy metabolism in eukaryotic cells"", Milan et al. (2000) had identified a likely positional coding sequence. Noting this coding sequence's similarity with, but distinctness from, the only two human genes then known to encode the gamma subunit of AMPK, namely PRKAG1 and PRKAG2, Milan et al. (2000) named their new gene PRKAG3. Sequencing of this gene in the RN genotypes revealed the causative mutation to be a missense mutation (c.599G>A) resulting in a ""nonconservative substitution (R200Q)"". The following year, Ciobanu et al. (2001) showed that one of the other alleles at this locus, namely I199V (first reported by Milan et al., 2000) has a substantial effect on glycogen content and meat quality in populations for which the R200Q allele is not segregating. " "Using a genome scan with 63 markers, Milan et al. (1995) mapped the RN locus to chromosome SSC15, 18cM from marker S008. Fine-mapping on SSC15 by Milan et al. (1996) narrowed the location to ""between markers Sw120 and Sw936, at 2 cM from Sw936 (LOD = 38.1)"". These same authors also physically mapped Sw936, and hence RN, to SSC15q21-22. In an independent study involving a genome scan with 19 microsatellites and one other marker, Mariani et al. (1996) also mapped the RN locus to SSC15, and then fine-mapped it with a further three microsatellite markers. The closest marker, Sw936, is 4.8cM from RN. Noting that the next-nearest marker (S0088; 10.6 cM from RN) is 3cM from the DPP4 gene, which had been physically mapped to SSC15q2.1, Mariani et al. (1996) concluded that RN is located in the region SSC15q2.1-15qtel. " 9825
OMIA:001449 By some excellent biological detective work, Eriksson et al. (2008) have shown the yellow-skin gene to be the gene encoding beta-carotene dioxygenase 2 (BCDO2). Interestingly, the yellow allele that is so common in domestic chickens throughout the world actually orginates not from the red jungle fowl but from the grey jungle fowl, thereby indicating a hybrid origin of the domestic chicken. Because there are so many difference in the sequence between the two alleles, the actual causal difference has not yet been identified but it must be regulatory, since the authors show that the yellow skin allele is expressed in liver but not in skin. 9031
OMIA:001941 "Schütz et al. (2016) identified the likely causal mutation as ""a deletion of 138kbp, spanning position 93,233kb to 93,371kb on chromosome 9 (BTA9), harboring only dimethyl-adenosine transferase 1 (TFB1M). The deletion breakpoints are flanked by bovine long interspersed nuclear elements Bov-B (upstream) and L1ME3 (downstream), suggesting a homologous recombination/deletion event. TFB1M di-methylates adenine residues in the hairpin loop at the 3’-end of mitochondrial 12S rRNA, being essential for synthesis and function of the small ribosomal subunit of mitochondria."" The causality of this deletion is reinforced by the fact that homozygous TFB1M knockout mice are not viable and suffer fetal death (Schütz et al., 2016)." "Using a strategy similar to that of VanRaden et al. (2011), Cooper et al. (2013) discovered reduced-fertility haplotype HH5, located on chromosome BTA9.
In their table of reduced-fertility haplotypes, Cole et al. (2014) list this haplotype as being located at 92,350,052 – 93,910,957bp on chromosome BTA9.
Schütz et al. (2016) fine-mapped the likely causal region of HH5 to be ""an approximately 138kb region spanning 93.233Mb to 93.371Mb""." 9913
OMIA:000262 By cloning and sequencing a very likely candidate gene (based on knowledge that the bovine disorder is due to deficiency of uridine monophosphate sythetase), Schwenger et al. (1993) identified a C>T transition in the bovine UMPS gene as a causal mutation. "The UMPS gene has been mapped to the middle of chromosome 1 (q31-36) (Barendse et al., 1993; Friedl and Rottmann, 1994; Ryan et al., 1994). [Compiled by Imke Tammen]
In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) confirmed the mapping of this disorder to BTA1 at 55-73Mb (UMD 3.0 genome assembly)." 9913
OMIA:001279 "Parker et al. (2017) identified a likely causal mutation (""SGK3^Val96GlyfsTer50""): a ""deletion [that] removes four bases (TTAG) from chr29 : 16366702–16366705 within exon 4 of the serum/glucocorticoid regulated kinase family member 3 gene (SGK3). This deletion alters the reading frame of the protein at amino acid 96 creating a new protein sequence for 50 amino acids and a premature stop at amino acid 157. This mutation is predicted to knock out the original function of the gene as it removes the entire STKc_SGK3 catalytic domain for which the gene is named. . . . the 4 bp deletion . . . was resequenced in 12 hairless AHT [American Hairless Terrier] and four coated Rat Terriers . . . . All hairless AHT were found to have two copies of the mutation, while the four coated Rat Terriers were wild-type at both alleles""." "Parker et al. (2017) mapped this trait to a region ""greater than 4.8 Mb from chr29 : 15973319–20794824 in the CanFam3.1 assembly""." 9615
OMIA:001694 "Yoshikawa et al. (2016) ""demonstrated that feline A3Z3 hap V is maintained under conditions of positive selection and is resistant to FIV Vif-dependent degradation. . . . To the best of our knowledge, this is the first report providing evidence of the evolutionary arms race between domestic cat and its lentivirus FIV"". The likely causal variant for resistance is 65I." 9685
OMIA:001728 31033
OMIA:000685 "By sequencing two positional functional candidate genes, Rinz et al. (2015) concluded that a likely causal mutation in Jack Russell Terriers is ""a single base insertion [c.633_634insC] in exon 7 of CHRNE that predicts a frameshift mutation and a premature stop codon [p.Gly212Argfs*274]"".
Herder et al. (2017) investigated a litter of Heideterriers (a ""nascent"" breed not recognized by the FCI), in which 4 out of 11 puppies showed pronounced muscle weakness. Only one of these puppies was available for genetic analysis. Herder et al. (2017) performed whole genome sequencing and identified a homozygous single nucleotide insertion into the coding sequence of the CHRNE gene (XM_014113502.1:c.1436_1437insG). The insertion was predicted to lead to a frameshift and premature stop codon (XP_013968977.1:p.Ser479ArgfsTer14). This variant was absent from the genomes of 274 control dogs. Based on the earlier findings in Jack Russell Terriers and other species, Herder et al. (2017) concluded that ""it is plausible that the CHRNE variant may have caused a myasthenia gravis-like disease in the investigated puppy.""" 9615
OMIA:001210 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Ginzinger et al. (1996) showed that the causal mutation for this disorder is ""a point mutation in amino acid residue 412 (Gly412Arg) in the COOH terminus of the cat LPL gene. This residue corresponds to codon 409 in the human LPL gene and is highly conserved in the LPL genes of at least seven other species""" 9685
OMIA:002073 "As explained by Shanthalingam et al. (2016), ""the signal peptide of CD18 [encoded by ITGB2], an adhesive protein expressed on the surface of leukocytes of cattle and other ruminants, is not cleaved. Intriguingly, leukotoxin produced by Mannheimia haemolytica binds to the intact signal peptide and causes lysis of ruminant leukocytes, resulting in acute pneumonia. In this proof-of-principle study, we used precise gene editing to induce a single amino acid substitution in CD18, which resulted in the cleavage of the signal peptide and abrogation of leukotoxin-induced cytolysis of leukocytes of the gene-edited bovine fetus. This report demonstrates the feasibility of developing lines of cattle genetically resistant to M. haemolytica-caused pneumonia, which will have significant impact on the sustainability of food-animal production in the United States and elsewhere. """ 9913
OMIA:001736 Genotyping of the three affected daughters with a 777,000 SNP chip, combined with whole-genome sequencing of one of the affected daughters, enabled Capitan et al. (2012) to identify the causative mutation as a 3.7Mb deletion encompassing the genes ARHGAP15, GTDC1 and ZEB2. Comparison with the homologous human disorder (see MIM entry above) implied that the syndrome is primarily due to the deletion of ZEB2. "Capitan et al. (2012) conducted a genome scan with a 50,000 SNP chip on the proband Charolais bull V, ""19 unaffected progeny, three affected daughters and their dams"". This highlighted a 2.8Mb region on chromosome BTA2 which showed a cluster of loci showing errors of Mendelian inheritance, suggestive of a deletion. " 9913
OMIA:001952 Qiao et al. (2015): c.451delinsTC 9825
OMIA:000690 In the first example of an inherited disorder in domesticated animals being shown to be due to an expanded repeat, and following a comparative positional cloning strategy (see Mapping section above), Lohi et al. (2005) reported affected Miniature Wirehaired Dachshunds as having 19 to 26 copies of a sequence of 12 nucleotides (12-mer; dodecamer) in the canine EPM2B gene (now called NHLRC1). This repeat occurs only twice or three times in normal dogs of a wide range of breeds. Hajek et al. (2016) reported the same expansion variant in two affected Beagles. "Lohi et a. (2005) undertook a ""genome-wide scan genotyping 241 canine specific microsatellite markers (http://research.marshfieldclinic.org/genetics/) spanning the entire canine genome in the 14 affected dogs and four unaffected relatives"". In dping so, they mapped the locus for this disorder to a region of CFA35 orthologous with the genes which are mutated in human Lafora's disease (EPM2A and EPM2B)." 9615
OMIA:001721 "Kaelin et al. (2012) reported the causal mutation as ""a base pair insertion in exon 20 [of the cheetah Taqpep gene], predicting a frameshift that replaces what would normally be the carboxy-terminal 16 amino acids with 109 new residues (N977Kfs110""." 32536
OMIA:000882 "By cloning and sequencing a very likely candidate gene (based on detailed biochemical comparisons of affected and normal Irish Setter dogs), Suber et al. (1993) reported a causative mutation as being ""a nonsense amber mutation at codon 807 (a G-->A transition converting TGG to TAG), which was confirmed to be present in putative exon 21 of the affected beta-subunit gene [PDE6B]. The premature stop codon truncates the beta subunit by 49 residues, thus removing the C-terminal domain that is required for posttranslational processing and membrane association.""" 9615
OMIA:000701 "Mou et al. (2011) showed that this mutation is due to a large insertion approximately 260kb downstream from the BMP12 gene (now known as GFD7), increasing the expression of this gene in embryonic skin. In the words of the authors: ""We find that in chickens a bare neck is caused by increased production of BMPs, factors previously implicated in defining the size of the gaps between neighboring feathers. Selective production of retinoic acid by embryonic neck skin enhances BMP signaling, thereby bringing this skin region close to the threshold of BMP action required to completely suppress feather development. This usually innocuous distinction between neck and body skin enables mutations that increase BMP action to render the neck completely bare while permitting normal feathering on the body.""" 9031
OMIA:001565 Flisikowski et al. (2010) described a Finnish Ayrshire bull with an incidence of almost 50% of late abortion/stillbirth in his progeny. A half-sib linkage analysis with the BovineSNP50 BeadChip implicated the maternally imprinted PEG3 domain on chromosome BTA18. Genes in this region are not expressed when inherited from the female parent. Close examination of this region disclosed that this bull was heterozygous for a 110 kb deletion in the MIMT1 gene. All of his offspring will have received a non-functional (maternally imprinted) version of this gene from their dam. The 50% of his offspring that receive the deletion from the bull will therefore have no functional MIMT1 gene. The vast majority of these offspring die in late pregnancy, resulting in late abortion/stillbirth. From a gene-expression study in affected and normal foetuses, Flisikowski et al. (2012) implicated a number of genes, especially NRSP1, which encodes neuropeptide S receptor 1. 9913
OMIA:001817 Exome sequencing in the candidate region (see Mapping section) of 2 affected, one carrier and one homozygous normal animal enabled Hirano et al. (2013) to identify the causal mutation as a missense mutation (c.235G>C; p.Val79Leu) in the IARS gene which encodes isoleucyl-tRNA synthetase. Hirano et al. (2013) conducted a genome scan on 30 affected and 30 normal offspring of a bull with an abnormally high incidence of this disorder, each offspring and the bull being genotyped with BovineSNP50 BeadChip, yielding 13,208 informative SNPs. Homozygosity mapping (supported by linkage mapping on the candidate chromosome) implicated a 4.04Mb region on chromosome BTA8, encompassing 29 annotated genes. 9913
OMIA:000542 Murgiano et al. (2015) investigated a family of Pezzata Rossa cattle with 4 affected cows. The pedigree was suggestive of X-linked semi-dominant inheritance with lethality in hemizygous mutant males. Two autosomal segments on chromosome 7 and 14 also showed positive LOD scores in a linkage analysis and could not definitively be excluded. Whole genome sequencing of one affected cow at 28x coverage and comparison to the 1000 bull genomes' sequence data identified two private coding variants in the critical intervals on BTA 7, 14, and X. These variants were a missense variant in ERCC6L and a splice site variant in TSR2. Expression analysis in mouse embryos demonstrated specific expression of TSR2 in developing hair-follicles whereas ERCC6L was not found to be expressed in hair follicles. Therefore, the authors concluded that the TSR2 variant (c.441+226A>G), which changed the conserved 3'-splice site of intron 4 from AG into GG, is the most likely causative variant. The authors analyzed the TSR2 transcripts in biopsies from lesional (hairless) and non-lesional skin areas from affected cows. The splice site variant leads to aberrant splicing with either retention of intron 4 or to a lesser degree activiation of a cryptic splice site within exon 5. The proportion of mutant transcripts was much higher in hairless skin compared to hairless skin, which is most likely due to a higher percentage of active X-chromosomes with the mutant allele. The transcript analysis thus provided very strong support for the causality of the TSR2 variant. "As noted by Eldridge and Atkeson (1953), this is ""the first character to be reported in dairy cattle for which the causative gene can be quite definitely located on a specific chromosome"" (because of their data supporting X-linked inheritance) and consequently ""the gene for streaked hairlessness becomes a marker for one linkage group, and thus is the first step towards building a chromosome map for cattle""." 9913
OMIA:001160 "Using the candidate gene strategy (based on the characteristic hypercholesterolemia due to deficiency of LDL receptors), Yamamoto et al. (1986) compared the cDNA sequence of the LDL receptor in WHHL and normal rabbits, and discovered the causal mutation to be ""an in-frame deletion of 12 nucleotides that eliminates four amino acids from the cysteine-rich ligand binding domain of the LDL receptor""." 9986
OMIA:000418 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Kishnani et al. (1997) showed that the causative mutation in dogs is a G to C transversion in the G6PC (glucose-6-phosphatase) gene that changes the amino acid codon from methionine to isoleucine (M121I), producing a variant of the enzyme with ""15 times less enzyme activity""." CFA9 9615
OMIA:002090 "Agerholm et al. (2017): ""whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire.""" "Agerholm et al. (2017): ""High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26""" 9913
OMIA:001464 "Recognising the close resemblance of this disorder in Chianina cattle to Brody disease in humans, Drogemuller et al. (2008) illustrated the power of the candidate-gene approach by showing that this disorder in Chianina cattle is due to a missense mutation in the bovine version of the ""Brody gene"" - ATP2A1.
Interestingly, another mutation in this same gene causes a far more severe set of clinical signs: congenital muscular dystonia 1 (OMIA 001450-9913).
The situation has been complicated somewhat with the discovery by Grunberg et al. (2010) of a Dutch Improved Red and White cross-bred calf with clinical signs of PMT yet with the same mutation as seen in the Belgian Blue with congenital muscular dystonia 1 (OMIA 001450-9913). They raise the very real (and not unexpected) possibility that the same mutation can have different effects in different breeds. Dorotea et al. (2015) shed some light on this enigma.
Murgiano et al. (2012) identified the causal mutation in Romagnola cattle as two separate missense base substitutions in ""exon 8 (c.[632 G>T; 857 G>T])"" resulting in two amino-acid substitutions ""(p.[(Gly211Val; Gly284Val)])"" at highly conserved residues. Interestingly, only one of the four affected calves in this study was homozygous for the newly-identified double mutation; the other three affected calves were compound heterozygotes for the double mutation and the ""exon 6 variant c.491 G>A(p. Arg146Gly)"" reported by Drogemuller et al. (2008) in Chianina cattle." 9913
OMIA:001573 "Cruz Cardona et al. (2011) reported the first identified case of an animal equivalent of ""Philadelphia chromosome"" - a chromosomal translocation that results in chronic leukemia. This translocation involves the gene known as breakpoint cluster region (BCR)." 9615
OMIA:001821 "Sequencing of the candidate gene in one white and one standard Doberman Pincher ""revealed a 4,081 base pair deletion resulting in loss of the terminus of exon seven of SLC45A2 (chr4[ratio]77,062,968–77,067,051)"" (g.27141_31223del (CanFam2)) as a highly likely causative mutation (Winkler et al., 2014). As also reported by Winkler et al. (2014), ""This mutation is predicted to cause the last 50 amino acids of exon 7 to be replaced by 191 new amino acids before an in-frame stop codon is found, as predicted from the canine reference genome (CanFam2.0) . . . . This deletion also removes the poly-A addition signal (AATAAA), and the next predicted polyadenylation signal for the mutant chromosome is 6,106 bp downstream from the new stop codon.""
Wijesena and Schmutz (2015): c.1478G>A; p.G493D in exon 7 in a female albino Lhasa Apso and in ""an albino Pekingese, 2 albino Pomeranians, and an albino mixed breed dog that was small and long haired""" Based on the very strong phenotypic resemblance between the white phenotype of Doberman Pinschers and oculocutaneous albinism (OCA) in humans, Winkler et al. (2014) obtained flanking markers from the canine genome assembly for the canine orthologues of four of the genes involved in OCD in humans, namely tyrosinase (TYR) for OCA1, P-gene for OCA2, tyrosinase-related protein 1 (TYRP1) for OCA3, and solute carrier family, member 2 (SLC45A2) for OCA4. An exclusion analysis involving 20 white and 20 standard Doberman Pinchers eliminated all but the last candidate gene. 9615
OMIA:001827 "For eight of the nine haplotypes with a significant effect on calving rate (see Mapping section), Fritz et al. (2013) searched for causal mutations via whole-genome sequence data from 25 Holstein, 11 Montbéliarde and nine Normande bulls which had made major contributions to their breed. Specifically, they filtered ""for mutations that were (a) located at+or –6 Mb from the detected haplotype (b) carried in the heterozygous state by the carrier bulls and (c) absent from the non carrier bulls from the three breeds"" and then examined identified polymorphisms for their likely effect on protein structure and function. For MH1, Fritz et al. (2013) provided strong evidence for a candidate causal mutation, namely a nonsense mutation (g.27956790C>T; UMD 3.1 genome assembly) in the SHBG gene (which encodes sex-hormone binding globulin), leading to p.Q52X.
Reinartz and Distl (2016) reported this mutant occurring in Vorderwald cattle with Montbéliarde ancestry, including in one live animal that is homozygous for this mutant." "By analysing Illumina Bovine 50k Beadchip genotype data from 47,878 Holstein, 16,833 Montbéliarde and 11,466 Normande cattle in the French genomic selection database, Fritz et al. (2013) identified 34 common (>1%) haplotypes that have a significant deficit (P<10^-4) of homozygotes in live animals, and which are, therefore, each likely to harbour a deleterious mutation. Three of these haplotypes, namely BY (Brachyspina; OMIA 000151-9913), HH1 (OMIA 000001-9913) and HH3 (OMIA 001824-9913), had been reported by VanRaden et al. (2011; J Dairy Sci 94:6153-61). Following the convention of naming such haplotypes with a first letter indicating breed, a second letter H for haplotype, followed by a sequential number, Fritz et al. (2013) named their 14 new Holstein haplotypes as HH4 to HH17, their 11 Montbéliarde haplotypes as MH1 to MH11, and their six Normande haplotypes as NH1 to NH6. Analyses of reproductive data indicated that nine of the 34 haplotypes have a significant effect on fertility, including six of the newly identified haplotypes, namely HH4, HH5, HH6, MH1, MH2 and NH5.
This present OMIA entry is for MH1, which is located in chromosome BTA19, at 27.6–29.4Mb (UMD 3.1 genome assembly) (Fritz et al., 2013)." 9913
OMIA:001354 "Sequencing within the refined candidate region (described in the Mapping section above) enabled Freking et al. (2002) to identify the causative mutation as a ""a single A/G polymorphism located at position 103,894 of GenBank AF354168 and position 267 of the GenBank STS AF401294"". A few months later, Smit et al. (2003), working on in an independent sheep resource, identified the same mutation, which they described as ""an A-to-G transition in a highly conserved dodecamer motif between DLK1 and GTL2"".
By 2010, knowledge of this most unusual mutant could be summarised as follows. ""The mutation is a base substitution in a non-coding section of a 90-kb region of DNA that contains six genes: DLK1, DAT, and PEG11 have paternal allele-specific expression whereas GTL2, PEG11AS and MEG8 are expressed from the maternal allele. When an animal inherits the callipyge mutation from its sire but not its dam, the mutation increases the expression of the DLK1 and PEG11 genes on the same (paternal) chromosome; the mutation is said to be cis-acting. The increased expression of these two genes is associated with the muscle hypertrophy of the callipyge trait."" (Nicholas, 2010; Introduction to Veterinary Genetics, Wiley-Blackwell, Oxford; p. 202)" "In the absence of any useful sheep markers, Cockett et al. (1994) conducted a ""genome scan"" with just four(!) bovine minisatellites (VNTRs), two of which had no known bovine map location, the other two of which were known to be located on bovine chromosomes BTA21 and BTA26. To the authors' understandable surprise (not to mention extraordinary luck), the BTA21 marker (GMBT16) showed linkage with the CLPG locus! Linkage analysis in additional families confirmed that GMBT16 is linked to CLPG with theta = 20%. Since GMBT16 had also been ISH-mapped to the pro-terminal region of sheep homologous chromosome OVA18, Cockett et al. (1994) had succeeded in mapping the CLPG locus! The same authors then used bovine microsatellites and additional bovine minisatellites, all known to be on BTA21, to fine-map the CPLG locus to within 3 cM of bovine microsatellite CSSM18 on OVA18. Freking et al. (1998) confirmed the map location of CLPG in a resource flock derived from Dorset rams and Romanov ewes. Extensive fine-mapping effort in the following years finally yielded two ovine BACs and a connecting PCR product that together spanned a 250kb region including the CLPG locus (Charlier et al. (2001). Sequencing of this region revealed six imprinted transcripts: ""DLK1, DAT, and PEG11 were shown to be paternally expressed and GTL2, antiPEG11, and MEG8 to be maternally expressed"". Four of these (PEG11, MEG8, asDAT and antiPEG11) were novel genes." 9940
OMIA:001692 "Kyöstilä et al. (2012) reported the causative mutation as being a ""missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain"" of the SEL1L gene, whose peptide is a ""component of the endoplasmic reticulum (ER)–associated protein degradation (ERAD) machinery"". Since mutations in this gene have not previously been reported in any species, this discovery provides a new potential candidate gene for human progressive childhood ataxias." "As reported by Kyöstilä et al. (2012), ""A genome-wide association study [GWAS] in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8""." 9615
OMIA:001429 "By conducting an association analysis with SNPs in the 5MB candidate region of the Tabby locus on chromosome FCAA1 (see Mapping section above), Kaelin et al. (2012) narrowed the hunt down to a 244kb region containing three coding sequences, one of which had not been described previously in the cat. Sequencing cats of various tabby phenotypes revealed a range of causal mutations in the ""new"" gene, which the authors named Transmembrane Aminopeptidase Q (Taqpep). They named its peptide product Tabulin, to reflect its key role in tabby phenotypes. Using a slightly different nomenclature for tabby alleles, Kaelin et al. (2012) reported that ""most blotched cats carried a nonsense mutation, W841X . . . in exon 17 of the third gene [i.e. Taqpep]. We subsequently identified two additional variants in the same gene, S59X and D228N . . . . This gene [Taqpep] is expressed in developing felid skin, and its loss of function causes a loss of color pattern periodicity without obvious effects on other organ systems. . . . In feral cats, we observed homozygosity or compound heterozygosity for the Ta^b S59X or W841X alleles in 58 out of 58 (58/58) blotched animals [Ta^b/Ta^b], with no phenotypic distinction among the different genotypic classes, compared to 51/51 mackerel cats [Ta^M/Ta^M or Ta^M/Ta^b] that carried 0 or 1 Ta^b alleles . . . A third Ta^b allele, D228N, was found to cosegregate with the blotched phenotype in a research colony"". In summary, Kaelin et al. (2012) reported three blotched tabby (Ta^b) alleles, namely S59X, D228N and W841X, in the gene named Transmembrane Aminopeptidase Q (Taqpep). The ""wild type"" allele at this locus, i.e. with S59, D228 and W841, is the mackerel tabby allele, Ta^M.
Jackson (2013) provides a very informative summary of the results of Kaelin et al. (2012).
The gene name ""Taqpep"" has been replaced by laeverin with symbol LVRN." By examining the segregation of pairs of tabby alleles in three pedigrees, Eizirik et al. (2010) showed that at least three loci are involved in determining the tabby pattern. A gene (not then identified) in a 5Mb region of cat chromosome FCAA1 accounts for the two main tabby alleles, namely mackerel (T^a) and blotched (t^b). Eizirik et al. (2010) suggested calling this locus the tabby locus. They also show that the T^a allele maps to a 3.8Mb region, now called the Ticked locus, on cat chromosome FCAB1, thereby refining the mapping result of Lyons et al. (2006); see Coat Colour, Ticked (OMIA 001484-9685). The spotted phenotype appears to be due to the action of one or more modifying loci, as yet unmapped. 9685
OMIA:001097 "The most likely positional candidate gene in the CFA region (see Mapping section) was SLC19A3, which ""controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2"" (Vernau et al., 2013). Having determined that this gene is duplicated in that region of the dog genome, Vernau et al. (2013) showed that the first of these, SLC19A3.1, has a higher sequence similarity to the corresponding human gene, and, unlike the second, is expressed in relevant tissues, namely cerebrum, cerebellum and spinal cord. Sequencing of the coding regions of SLC19A3.1 in affected dogs and in one control revealed four differences, one of which, a frameshifting ""4 bp insertion (c.624 insTTGC) and SNP (c.625 C>A) in exon 2"", was subsequently shown to segregate perfectly with the disorder genotype, and to not be present in other breeds: ""All 11 dogs with AHE were homozygous for the mutation, 26/41 unaffected AH dogs were homozygous wild type and 15/41 unaffected AH dogs were determined to be heterozygous carriers. In order to determine if the insertion was just a polymorphism, 187 dogs from 51 breeds were genotyped and the mutant allele was not identified."" (Vernau et al., 2013)" "A GWAS was conducted by Vernau et al. (2013) on 8 affected Alaskan Huskies and 20 unaffected, related controls, each genotyped with the Illumina HD canine array, yielding 114,613 SNPs that were included in the analysis. The analysis highlighted one region on chromosome CFA25. Homozygosity mapping narrowed the region to ""3.5 Mb between 41074763 and 44542154"". " 9615
OMIA:001472 The causative mutation is a single nucleotide deletion (c.325delC) in exon 4 of TPP1, which causes an amino acid codon frameshift and a premature stop codon (Awano et al., 2006). There is an analogous disease in humans (OMIM# 204500). CFA21 9615
OMIA:001428 "Starting with a list of candidate genes based on comparative clinical signs in other species (especially humans), Shearman and Wilton (2011) used linkage analysis to eventually narrow the field down to the VPS13B gene. They ""sequenced each of the 63 exons of VPS13B in affected and control dogs and found that the causative mutation in Border collies is a 4 bp deletion in exon 19 of the largest transcript that results in premature truncation of the protein.""" 9615
OMIA:001902 "As reported by Pausch et al. (2014), ""whole-genome re-sequencing data of 43 animals revealed a candidate causal nonsense mutation (rs378652941, c.483C>A, p.Cys161X) in the transmembrane protein 95 encoding gene TMEM95 which was subsequently validated in 1990 AI bulls. Immunohistochemical investigations evidenced that TMEM95 is located at the surface of spermatozoa of fertile animals whereas it is absent in spermatozoa of subfertile animals"". Only ""1.7% of 35,671 inseminations"" were successful in bulls that are homozygous for the mutation. " "A GWAS by Pausch et al. (2014) for male reproductive ability (ranging ""from −40 to +13 and reflect[ing] the bulls' reproductive performance as percentage deviation from the population mean, based on 15 million artificial inseminations"") on 7961 Fleckvieh AI bulls, each with imputed genotypes of 652,856 SNPs, highlighted a region on chromosome BTA19. Subsequent autozygosity mapping narrowed the region to 1386 kb. " 9913
OMIA:002099 "Bauer et al. (2017): ""Comparing the genome sequence of the affected dog with 288 genomes from genetically diverse non-affected dogs we identified a private heterozygous variant in the ASPRV1 gene encoding ""aspartic peptidase, retroviral-like 1"", which is also known as skin aspartic protease (SASPase). The variant was absent in both parents and therefore due to a de novo mutation event. It was a missense variant, c.1052T>C, affecting a conserved residue close to an autoprocessing cleavage site, p.(Leu351Pro). "" The authors showed altered filaggrin processing in the affected dog with the ASPRV1 variant. Filaggrin is important for skin integrity and variants in the filaggrin gene lead to ichthyosis vulgaris in humans." 9615
OMIA:001514 """Targeted high-throughput sequencing of [the positional candidate segment] in 4 affected and 4 unaffected dogs"" enabled Plassais et al. (2016) to identify 478 variants, only one of which ""perfectly segregated with the expected recessive inheritance in 300 sporting dogs of known clinical status, while it was never present in 900 unaffected dogs from 130 other breeds. This variant, located 90 kb upstream of the GDNF gene, a highly relevant neurotrophic factor candidate gene, lies in [the last exon of] a long intergenic non-coding RNAs (lincRNA), GDNF-AS."" The authors also reported that "" Functional analyses (qRT-PCR, EMSA) confirmed that the mutation alters the binding of regulatory complex, leading to a significant decrease of both GDNF and GDNF-AS mRNA expression levels.""" "Plassais et al. (2016) ""highlighted a common homozygous haplotype of 1.8 Mb (chr4:70,6–72,4Mb) shared by all affected dogs in the four sporting breeds (listed in this entry)""" 9615
OMIA:002064 "Aberdein et al. (2017): insertion ""of an adenine within exon 3 of the FAS-ligand gene"" (c.413_414insA) at location 14607400 on chromosome FCA F1, resulting ""in a frameshift and a predicted premature stop codon at position 176 of the 280 amino acid protein chain (p.Arg140Lysfs*37)""" 9685
OMIA:001481 "Tanaka et al. (2015): ""a missense mutation in exon 7 (c.C1270T/p.R424W) in the German shepherd breed and a 3nt deletion in exon 7 (c.1931_1933delTGG/p.V644del) in Labrador retrievers""" 9615
OMIA:000363 "A molecular basis for this disorder was first reported by Tcherneva et al. (2006): ""The first non-coding and 10 of the 14 coding exons of the sequenced canine FXI gene were identical between the normal KBTs’ DNA and the published canine genome sequence. However, the seventh coding exon differs between normal and affected animals. It is normally 110 bp long, but in affected KBTs it contains a short interspersed nucleotide element (SINE) insertion. This exonic SINE is 90 bp long, consisting mostly of adenines coding for lysine which is presumed to affect the 3rd apple domain of the FXI gene.""" 9615
OMIA:001309 By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Yogalingam et al. (2002) identified a single bp insertion (708-709insC) in the canine SGSH gene as a causative mutation. 9615
OMIA:001725 "By sequencing a key candidate gene (a receptor for a range of viruses), Wan et al. (2012) discovered that resistance to grass carp reovirus is due to a 15-bp deletion in the coding region of the Ctenopharyngodon idella Retinoic acid-inducible gene I (CiRIG-I). As the authors reported: ""The deletion mutation cancels a predicted phosphorylation site and changes the secondary structure and the probability of peroxisomal targeting signal 1 in CiRIG-I."" " 7959
OMIA:000915 "Mochii et al. (1998): ""a two-base deletion resulting in premature termination of the polypeptide in the region following the zipper region""
Minvielle et al. (2010) confirmed this variant" 93934
OMIA:001745 "Utilising extensive genome sequence data from tens of pigs, Rubin et al. (2012) showed that Hampshire pigs (belted phenotype) have ""a 4.3-kb duplication (DUP2) located ∼100 kb upstream of KIT and a 23-kb duplication (DUP3) ∼100 kb downstream of KIT, which in turn contained a fourth ∼4.3-kb duplication (DUP4) not present on wild-type chromosomes"". Across four breeds, belted pigs always had DUP2 and DUP4, but some lacked DUP3. The authors ""conclude that DUP2–4 is strongly associated with the presence of the Belt and propose that one or more of these duplications are required for manifestation of the Belt phenotype . . . DUP2 is the strongest causative candidate because it overlaps with one of the most well-conserved noncoding regions located upstream of KIT"". " From a genome scan with 65 microsatellite markers on 67 backcross offspring from matings between non-belted sires and F1 (belted x non-belted) dams, Giuffra et al. (1999) linkage-mapped the belt locus to the centromeric region of chromosome SSC8, which contains two potential candidate genes, namely KIT and EDNRA. They then showed complete co-segregation of the belt phenotype with a SNP at position 2678 of exon 19 of the KIT gene, which strongly suggested that belt is an allele at the KIT locus. This study established for the first time that Belt is an allele to the Dominant white allele (see OMIA 000209-9825). Before this study Belt and Dominant white were considered to be two independent loci in the pig. (with thanks to Leif Andersson) 9825
OMIA:001138 "By cloning and sequencing a very likely candidate gene (based on knowledge of the biochemical and physiological properties of the enzyme catalase in affected dogs), Nakamura et al. (2000) reported that the canine disorder in Beagles is due to a missense mutation [in the catalase gene (CAT),] leading to the substitution of alanine(327) (GCT) by threonine (ACT)""." 9615
OMIA:000380 9031
OMIA:001135 "Building on the mapping results of Kobayashi et al. (2000) (see Mapping section above), Hirano et al. (2000) did some further fine mapping, and then constructed a cosmid library of the fine-mapped region of BTA1, and then used the best cosmid clone as a probe of kidney cDNA from normal and affected animals, identifying a single cDNA, which, when sequenced, turned out to be the bovine paracellin-1 gene, which they called Claudin-16, and which lacked exons 1-4 in affected animals. Independently, and building on the mapping results of Ohba et al. (2000; Mammalian Genome 11:316-319), Ohba et al. (2000; Genomics 68:229-236) did some further fine mapping and physical mapping of the region, and then identified and sequenced their comparative positional candidate gene, paracellin-1, revealing ""a region of 37 kb including exons 1 to 4 of the bovine paracellin-1 gene was deleted in the affected animals"". Thus both groups arrived at the same result at around the same time: the former paper was published in May 2000, and the latter in September 2000. " Two independent groups (Kobayashi et al., 2000; Ohba et al. 2000; Mammalian Genome 11:316-319) each used genome scans starting with more than 200 microsatellite markers to map the disorder to the central region of chromosome BTA1. Kobayashi et al. (2000) used a second set of 110 markers for fine-mapping, and then FISH-mapped a cosmid containing a relevant marker to BTA1q31-33. Ohba et al. (2000; Mammalian Genome 11:316-319) used homozygosity mapping to narrow the region to 4cM, and noted that this region is homologous to a region of human chromosome HSA3q that contains the gene paracellin-1 gene, mutations in which cause a related disorder in humans. Paracellin-1 thus became a comparative positional candidate gene. 9913
OMIA:002023 "By sequencing exons and flanking regions of the candidate gene SLC7A9 in affected cats, Mizukami et al. (2016) ""revealed 3 unique homozygous SLC7A9 missense variants: one in exon 5 (p.Asp236Asn) from a non-purpose-bred medium-haired cat, one in exon 7 (p.Val294Glu) in a Maine Coon and a Sphinx cat, and one in exon 10 (p.Thr392Met) from a non-purpose-bred long-haired cat. A genotyping assay subsequently identified another cystinuric domestic medium-haired cat that was homozygous for the variant originally identified in the purebred cats [p.Val294Glu]. These missense variants result in deleterious amino acid substitutions of highly conserved residues in the [encoded] bo,+AT protein"". " 9685
OMIA:001928 "Subsequent sequencing by Rinz et al. (2014) of the primary candidate gene (COLQ or LOC608697; see Mapping section above) revealed a causal mutation as ""a variant in exon 14 (c.1010T>C) that results in the substitution of a conserved amino acid (I337T) within the C-terminal domain. Both affected puppies were homozygous for this variant, and 16 relatives were heterozygous, while 288 unrelated Labrador Retrievers and 112 dogs of other breeds were wild-type."" " Having access to only two affected members of a single family, Rinz et al. (2014) were not able to conduct a GWAS to map this disorder. Instead they examined haplotype inheritance in the region of 18 comparative candidate genes (based on genes with known causal mutations for various types of CMS in humans), using relevant SNPs from the 173,662 SNPs in the Illumina CanineHD Infinium BeadChip, in the two affected littermates, five normal littermates and the two normal (but related) parents. Only one candidate gene (COLQ; officially known as LOC608697) [on chromosome CFA23] showed concordant inheritance. 9615
OMIA:001297 9615
OMIA:000662 "Genome-wide homozygosity mapping in a family in which this disorder was segregating led to Zhao et al. (2012) discovering the causal mutation as a ""missense mutation c.2909G>C on exon 21 of AGTPBP1"" which results in ""an Arg to Pro substitution (p.Arg970Pro) at amino acid 970, which is a conserved residue for the catalytic activity of AGTPBP1"". The authors also report that ""The ATP/GTP-binding protein 1 gene (Agtpbp1) has been shown to be related to Purkinje cell degeneration (pcd) phenotypes including ataxia in mice.""" 9940
OMIA:001350 "Armed with the strong assumption that FecX(H) is allelic with FecX(I) (see Mapping section above), and having identified BMP15 as a strong comparative positional candidate gene for FecX(I), Galloway et al. (2000) showed that the causative mutation for FecX(H) is a ""single C→T transition at nucleotide position 67 of the mature peptide coding region of FecXH carriers [which] introduces a premature stop codon in the place of glutamic acid (Q) at amino-acid residue 23 (residue 291 of the unprocessed protein) . . . Such premature truncation probably results in complete loss of BMP15 function.""" "As reported by Davis et al. (1995), ""Crossing FecXI with FecXH animals produces FecXI/FecXH infertile females phenotypically indistinguishable from FecXI/FecXI females"", suggesting that FecXI and FecXH are allelic at a single X-linked locus." 9940
OMIA:000636 By cloning and sequencing a very likely candidate gene (based on knowledge that the disorder is due to deficiency of Factor H), Hegasy et al. (2002) discovered that the molecular basis for this disorder is a missense mutation (T3610G) in the gene for factor H, resulting in an I1166R amino-acid substitution. [FN 13 Jan 2003; 21 Sep 2012] 9825
OMIA:001974 "As reported by Li et al. (2016) [published online in 2015], ""In the course of a reverse genetic screen in the Belgian Blue cattle breed, we uncovered a 10-bp deletion (c.87_96del) in the first coding exon of the melanophilin gene (MLPH), which introduces a premature stop codon (p.Glu32Aspfs*1) in the same exon, truncating 94% of the protein."" Belgian Blue cattle homozygous for this mutant (and with the appropriate genotype at the epistatic KIT locus) all exhibited a dilution coat colour phenotype (as expected with a mutation that inactivates MLPH), which the authors called ""cool gray""." 9913
OMIA:001360 "Being well aware of the role of mutations in FMO3/FMO6P being causal for this disorder in cattle (OMIA 001360-9913) and chickens (OMIA 001360-9031), Mo et al. (2013) cloned and sequenced the quail FMO3 gene, and identified ""a nonsense mutation ([c.992C>T]; Q319X) which was significantly associated with the elevated TMA content in quail egg yolks. Genotype TT at Q319X mutation loci was sensitive to choline. With addition of choline in the feed, the quails with homozygote TT at the Q319X mutation loci laid fish-odour eggs, indicating an interaction between genotype and diet. The results indicated that Q319X mutation was associated with the fishy off-flavor in quail eggs.""" 93934
OMIA:002032 "Forman et al. (2016): ""6.47 Mb inversion was identified with breakpoints in intron 3 of FAM134B (chr4:86,910,352) and in an upstream intergenic region (chr4:80,439,639) . . . All three cases were homozygous for the inversion and all 170 controls homozygous for the reference allele.""" 9615
OMIA:000876 "By cloning and sequencing a very likely candidate gene (based on knowledge that the disorder is due to deficiency of riboflavin-binding protein; ribBP), MacLachlan et al. (1993) identified a ""deletion in the rd ribBP cDNA correspond[ing] precisely to an exon. The splice site following this exon contains a G-->A mutation at position 1 of the downstream 5'-splice donor sequence. The effect of this anomaly and the cause of the rd phenotype is the loss of the 100-base pair exon during the splicing process."" " 9031
OMIA:001673 "As reported by Sironen et al. (2011), the 2 Mb region on SSc12 contained the gene TEX14, which was a strong candidate because mice in which this gene has been knocked out have a very similar phenotype to affected pigs. Sequencing of this gene in affected pigs ""revealed a 51 bp insertion within exon 27, which caused differential splicing of the exon and created a premature translation stop codon. The expression of Tex14 was markedly down regulated in the testis of a SA affected boar compared to control boars and no protein product was identified by Western blotting.""" From a genome-wide scan conducted with markers on the PorcineSNP60 Beadchip, Sironen et al. (2011) mapped this disorder to a 2 Mb region on chromosome SSC12. 9825
OMIA:001552 "By sequencing the likely positional candidate gene mentioned in the Mapping section (above), Farias et al (2011) identified the causative mutation as a single base deletion in ATP13A2, namely ""c.1,623delG, which predicted a frame shift and premature termination codon (p.P541fsX597)"".
Later that same year, Wöhlke et al. (2011) confirmed the same mutation, but called it c.1620delG, and stated that it ""causes an alternative splicing of exon 16 but not a frameshift mutation with a premature termination codon as previously supposed [by Farias et al., 2011]"". They went on to explain that ""As a result of the in-frame loss of exon 16, the ATP13A2 protein is shortened by 69 amino acids. Therefore, all NCL-affected Tibetan terriers in the present study can synthesize this shortened ATP13A2 protein. In humans, all three isoforms do not lack exon 16. This new insight on the structure of the mutated protein may explain why Tibetan terriers express only mild neurodegenerative symptoms and the onset of the disease is late in life.""" "By conducting a GWAS on 19 affected and 15 control Tibetan Terriers, each genotyped with the Affymetrix Canine Genome 2.0 Array, Farias et al. (2011) mapped this disorder to a 1.3 Mb region of chromosome CFA2., which contains 18 genes, including a likely candidate ATP13A2.
Later that same year, Wöhlke et al. (2011) reported an independent GWAS on 12 affected and 7 control Tibetan Terriers, each genotyped with the ""127K canine Affymetrix SNP chip"", which enabled them to map this disorder to the same region of CFA2 as Farias et al. (2011)." 9615
OMIA:002021 "Analysis of whole-genome sequence from ""4 female genomes predicted to be heterozygous at the BR1 locus and 60 control genomes, which should be either hemizygous or homozygous wildtype at the causative variant"" enabled Murgiano et al. (2016) to identify ""61 private variants in the critical interval, none of them located in an exon of an annotated gene. However, one of the private variants was close to an exon/intron boundary in intron 10 of the MBTPS2 gene encoding the membrane bound transcription factor peptidase, site 2 (c.1437+4T>C). Different coding variants in this gene lead to three related genodermatoses in human patients [see entries for ""Possible human homologues"" above]. We therefore analyzed MBTPS2 transcripts in skin and identified an aberrant transcript in a BR1 horse, which lacked the entire exon 10 and parts of exon 11. The MBTPS2:c1437+4T>C variant showed perfect co-segregation with the brindle phenotype in the investigated family and was absent from 457 control horses of diverse breeds. . . . The mutant transcript contained an open reading frame lacking 32 codons, which encode parts of the third luminal and the entire sixth transmembrane domain of the MBTPS2 protein (p.422_453del). . . . The variant designation on the transcript level . . . is r.[=, 1265_1360del]""." "By genotyping 36 descendants of a Quarter Horse mare, with the Illumina 70 k SNP chip, Murgiano et al. (2016) mapped the BR1 locus to ""a 5 Mb segment on chromosome X spanning from positions 13,601,933 to 18,711,357 (EquCab2 assembly; markers BIEC2-1111129 - BIEC2-1112988)"" which includes 41 annotated genes." 9796
OMIA:002088 "Plassais et al. (2015) ""carried out mutation screening on several keratins [located in the candidate region of CFA9] in 14 affected dogs and 16 controls and identified a complex mutation in KRT16 corresponding to an insertion/deletion (indel) of four nucleotides and a separate 1 bp deletion 15 nucleotides downstream in exon 6 . . . . This complex indel results in an insertion of 1 bp in affected dogs and introduces a frameshift changing the sequence of 10 amino acids and creating a premature stop codon (p.Glu392*) in the open reading frame of the gene. This stop codon located in the 2B domain leads to the loss of the last 85 amino acids of K16, including the helix termination motif. . . . To confirm that this mutation is causative and specific to the Dogue de Bordeaux, [Plassais et al.] sequenced a set of 334 Dogues de Bordeaux with known clinical status. All affected dogs were homozygous for the complex mutation, and all unaffected dogs were either homozygous for the wild-type alleles or heterozygous (245/306 and 61/306, respectively). Furthermore, the mutated allele was never detected in a panel of 344 unaffected dogs from 80 different breeds."" " "From a linkage analysis of a Dogue de Bordeaux family comprising 14 affected and 54 normal dogs, each genotyped with the canine 173,000 Illumina SNP chip, Plassais et al. (2015) mapped this disorder to a 20Mb region of chromosome CFA9 that contains the ""type I keratin cluster""." 9615
OMIA:001677 "In four Belgian Blue calves, Sartelet et al. (2015) identified the causal mutation as a nonsense mutation [c.7825C>T] ""in the LAMA3 gene that creates a premature stop codon (p.Arg2609*) in exon 60, truncating 22% of the corresponding protein""." An 8.3 Mb region on chromosome BTA24 (Sartelet et al., 2015). 9913
OMIA:000213 "Careful examination of the whole-genomes sequence data from the three parents of the captive-bred family segregating for the white phenotype, combined with ""restriction-site-associated DNA sequencing (RAD-seq)"" of the 13 offspring in the same family, enabled Xu et al. (2013) to identify a candidate mutation in each of two genes in the candidate region (see Mapping section). Genotyping of other Bengal tigers (20 white and 110 wild-type) for both mutations revealed the causal mutation to be a missense mutation, namely a ""C-to-T transition in exon 7 in SLC45A2 (solute carrier family 45 member 2, also known as MATP or AIM-1), which corresponds to alanine-to-valine substitution at amino acid residue 477 (A477V)"". " Having shown no association between the white phenotype of Bengal tigers and polymorphisms in any of the obvious candidate coat-colour genes, Xu et al. (2013) undertook a herculean effort that is very much a sign of the times, namely whole-genome sequencing three Bengal tigers (which are parents in a captive-bred family), and, from the sequence data, identifying 509,220 SNPs, each of which was aligned to the tiger reference genome. They then performed a GWAS on 7 white and 9 wild-type tigers (from the same captive-bred family), each genotyped with the identified SNPs, yielding 172,554 informative SNPs. The GWAS mapped the white locus to two adjacent scaffolds (75 and 1458). Linkage mapping within these two scaffolds highlighted a 3.3Mb candidate region, which (according to the tiger reference genome) contains 23 genes. 74535
OMIA:001931 "Having access to tissue from just a single affected calf and its normal parents, and having noted the calf's resemblance to disorders in humans (see OMIM links above) and various animal species (including horse {OMIA 000214-9796, OMIA 001688-9796}, cattle {OMIA 000214-9913, OMIA 001680-9913, OMIA 001931-9913}, and dog {OMIA 000214-9615}) due to mutations in the MITF gene, Wiedemar and Drögemüller (2014) sequenced ""all exons of the MITF gene in the calf, mother and father . . . to look for possible de novo mutations"". Although no potential causal variants were detected, the authors did notice that ""there were three intronic and four exonic SNPs for which the father showed homozygosity for one allele, the mother for the other allele and, surprisingly, the calf was not heterozygous in these SNPs as expected but carried the maternal alleles only"", implying deletion of the paternal chromosome in the calf. Having verified correct parentage via the ISAG bovine parentage microsatellite panel, the authors genotyped the calf and its parents with the Illumina BovineHD BeadChip (777 962 SNPs), which revealed that of the 855 SNPs exhibiting non-Mendelian inheritance, 307 were located within a 17.2 Mb region of chromosome BTA22 containing the MITF gene, and for each of these markers, the calf had inherited only the maternal allele. Subsequent analysis of all BTA22 SNPs enabled Wiedemar and Drögemüller (2014) to conclude that this disorder is due to a de novo deletion of a 19.1 Mb region of BTA22 from 28 835 247–47 983 179 which ""contains 132 annotated genes and loci"" including MITF. It remains an open question as to whether the disorder is due solely to the deletion of MITF or to the deletion of some other genes as well. " 9913
OMIA:001954 Missense mutation: c.1288G>A; p.A430T; Chr20:50,618,958C>T (CanFam 3.1 assembly) (Kyöstilä et al., 2015) By conducting a linkage and homozygosity-mapping analysis, Kyöstilä et al. (2015) determined that the locus for this disorder is located in one of three regions on canine chromosomes 11, 13 and 20. Subsequent analysis of genome sequence in these three regions identified the causal mutation to be a C>T exchange on chromosome CFA20:50,618,958 (CanFam 3.1 assembly). 9615
OMIA:001298 "Zangerl et al. (2006) identified a novel gene that they called PRCD in a 106kb candidate region on CFA9. They also showed that ""a homozygous mutation (TGC>TAC) in the second codon shows complete concordance with the disorder in 18 different dog breeds/breed varieties tested""." Using the power of comparative mapping, Acland et al. (1998) showed that this disorder in dogs maps to the same location as the gene for retinitis pigmentosa 17 in humans. 9615
OMIA:001525 "By sequencing a likely candidate gene (based on clinical signs and pathology) in a single German Shepherd Dog that had been euthanased five years previously), Boudreaux et al. (2010) reported that a ""12-base pair insertion was identified in the coding region for KINDLIN3 in the affected dog but not in the canine genome sequence or the control dog sequences. This mutation is predicted to result in the insertion of amino acids RRLP within an alpha helix located in the Kindlin-3 pleckstrin-homology domain of the F2 band 4.1, ezrin, radixin, moesin (FERM) subdomain"". The KINDLIN3 gene is now known as FERMT3 (fermitin family member 3)." 9615
OMIA:001799 "Following the results described in the Mapping section, sequencing of BMP15 revealed six polymorphisms, one of which (1009A>C; N337H) was strongly associated with ovulation rate. Genotyping of this polymorphism in additional randomly chosen ewes confirmed the effect, with CC homozygotes having an average ovulation rate of 3.28 compared with 2.02 for CA and 1.52 for AA ewes, with corresponding averages for litter size being 3.05 for CC, 2.46 for CA and 1.84 for AA (Demars et al., 2013). Interestingly, the authors note that the high fecundity of homozygous mutant (CC) ewes is ""in striking contrast with the sterility exhibited by all other known homozygous BMP15 mutations""." Demars et al. (2013) conducted a GWAS by genotyping 29 hyper-prolific and 34 control Polish Olkuska ewes with the Illumina OvineSNP50 chip. A single region on the X chromosome, including the prolificacy gene BMP15, was highlighted. BMP15 was thus a highly likely positional candidate gene. 9940
OMIA:001987 "Lyons et al. (2016): c.5A>G; p.V2A in Japanese Bobtail
Xu et al. (2016) identified the same likely causal mutation in Chinese short-tailed feral cat, and confirmed it in Japanese Bobtail." 9685
OMIA:001926 "In a remarkable indication of the power of whole-genome sequence analysis, Daetwyler et al. (2014) identified a causal mutation for this disorder as a missense mutation (g.32475732G>A [UMD3.1 reference sequence]; p.Gly960Arg) in the COL2A1 gene (which encodes the alpha-1 chain of type II collagen), by comparing the sequence of only two affected calves with sequence from bulls in the 1000-bull-genome project. Noting that the disorder is most likely dominant, the authors ""filtered for heterozygous polymorphisms in the two affected calves that were (i) absent in the 1000 bull genomes project database (except for Igale [the sire of the two affected calves]), as none of the other bulls sequenced had been reported to carry the syndrome and most had been extensively progeny tested, and (ii) predicted modified the amino acid sequence of a protein"". This analysis yielded just two candidate mutations, only one of which was in a functional candidate gene, namely COL2A1. The authors then confirmed the causality of this mutation: ""Genotyping by PCR and RFLP of the g.32475742G>A mutation in ten additional affected calves showed perfect association between this mutation and the syndrome and suggested mosaicism in the Igale germ line, given the small proportion of affected calves and the fact that affected calves were heterozygous at this position. Finally, Sanger sequencing of the products from conventional PCR and nested PCR performed after PCR and RFLP definitively confirmed mosaicism for Igale at the locus"".
Agerholm et al. (2016) reported a different likely COL2A1 causal mutation in Danish Holstein cattle: g.32473300 G>A; c.2463 + 1G>A: ""This private sequence variant was predicted to affect splicing as it altered the conserved splice donor sequence GT at the 5’-end of COL2A1 intron 36, which was changed to AT. All five available cases carried the mutant allele in heterozygous state and all five dams were homozygous wild type. The sire VH Cadiz Captivo was shown to be a gonadal and somatic mosaic as assessed by the presence of the mutant allele at levels of about 5 % in peripheral blood and 15 % in semen""." On 14 February 2000, in a post to the Angenmap discussion group (http://www.animalgenome.org/community/angenmap/mail/view.php?f=db/1824), Eggen and Boichard reported that this disorder had been mapped (to an undisclosed site) and hence a DNA test (based on linked microsatellites) was available. 9913
OMIA:001497 "By sequencing a very strong comparative and functional candidate gene, Benkel et al (2008) showed that ""marbled mink carry a mutation in exon 4 of the TYR gene (c.1835C > G) which results in an amino acid substitution (p.H420Q). The location of this substitution corresponds to the amino acid position that is also mutated in the TYR protein of the Himalayan mouse. Thus, the marbled variant is more aptly referred to as the Himalayan mink.""" In mapping the TYR gene to chromosome NVI7q1.1-q1.3 in the context of the albino phenotype, Anistoroaei et al. (Anim Genet 39:645-8, 2008) also mapped the Himilayan trait. 452646
OMIA:001672 "Exon sequencing of the candidate gene AGXT in Coton du Tulear dogs by Vidgren et al. (2012) revealed a missense mutation to be the cause of this disorder; specifically ""a single base change (c.996G>A) that changed one conserved residue (p.Gly102Ser)"". " 9615
OMIA:000546 Credille et al. (2009) reported that this disorder in Jack Russells is due to a LINE-1 insertion in the TGM1 gene. 9615
OMIA:002031 "Metzger et al. (2016): ""Filtering analysis for variants with predicted high or moderate effects revealed a missense mutation in LEPREL1 1.2 Mb proximal to the region of the genome-wide association, which was shown to be significantly associated with LS. LS-affected Lundehund harbored the mutant LEPREL1:g.139212C>G genotype A/A whereas all controls of other breeds showed the C/C wild type.""" "Metzger et al. (2016): ""Comprehensive analysis of bead chip and whole-genome sequencing data for LS in the Lundehund resulted in a genome-wide association signal on CFA 34 and LS-specific runs of homozygosity (ROH) in this region.""" 9615
OMIA:001948 "Small deletion: ""a 4-bp deletion within exon 33 of the ITGB4 gene (c.4412_4415del;[ OAR11:54,849,767–54,849,770 bp; Oar v3.1]). The c.4412_4415del mutation causes a frameshift resulting in a premature stop codon at position 1472 of the integrin β4 protein"" (Suárez-Vega et al., 2015)" "By conducting a GWAS on 20 affected, 28 related normal and 48 unrelated normal Churra sheep, each of which had been genotyped with the Illumina OvineSNP50 BeadChip (yielding 44,785 informative SNPs), Suárez-Vega et al. (2015) mapped this disorder to chromosome OAR11, in the vicinity of marker rs410387229 at 54,939,690 bp (OARv3.1). Subsequent homozygosity mapping narrowed the region to ""an 868-kb homozygous segment, from 54,632,309–55,500,100 bp"". This implicated a very likely comparative locational candidate gene, namely ITGB4." 9940
OMIA:001467 Baranowska et al. (2009) showed that this disorder is due to a deletion of a single base (at position 5304) in the mitochondrial gene for transfer RNA for the amino acid tyrosine (called tRNA-Tyr). 9615
OMIA:000402 "A Genome-Wide Association Study (GWAS) for this disorder led Walker et al. (2012) to a region on chromosome OAR19 which is homologous to the region of human chromosome HSA3 that includes the candidate gene for this disorder, namely GLB1 which encodes β-galactosidase. Subsequent sequencing of the candidate gene by the same authors identified ""a G to T base pair substitution mutation in exon 6 of ovine GLB1 causing a cysteine to phenylalanine amino acid substitution"". " 9940
OMIA:001800 "Martinez-Royo et al. (2008) reported ""a new naturally occurring mutation in the BMP15 gene from the ovine Rasa Aragonesa breed is described. This mutation is a deletion of 17 bp that leads to an altered amino acid sequence and introduces a premature stop codon in the protein. Highly significant associations (P < 0.0001) were found between the estimated breeding value for prolificacy and the genotype of BMP15 in Rasa Aragonesa animals with high and low breeding values for this trait. As for other mutations in BMP15, this new mutation is associated with increased prolificacy and sterility in heterozygous and homozygous ewes respectively""." 9940
OMIA:001786 "Whole genome re-sequencing of one affected Border Collie revealed 17 non-synonymous variants in the critical interval. Two of these variants were perfectly associated with intestinal cobalamin malabsorption in Border Collies. Based on the known functions of the corresponding genes the CUBN:c.8392delC frameshift variant is most likely causative for intestinal cobalamin malabsorption in Border Collies. This variant causes a premature stop codon in the open reading frame of cubilin (p.Gln2798Argfs*3) and is predicted to represent a complete loss of function allele (Owczarek-Lipska et al. 2013). CUBN and AMN form a transmembrane protein complex termed ""cubam"", which is essential in the uptake of cobalamin from the intestinal lumen. A defect in one of these two proteins therefore leads to intestinal cobalamin malabsorption. Other independent mutations in either the CUBN or the AMN gene very likely are responsible for this phenotype in other dog breeds.
By sequencing CUBN as a very strong positional candidate gene (see Mapping section), Fyfe et al. (2013) identified the same mutation (c.8392delC; p. Gln2798Argfs*3) in their Border Collie families.
By comparing sequence of the two candidate genes (AMN and CUBN) from the CanFam 3.1 reference genome assembly with sequence of the same two genes from the 15x whole-genome sequencing (WGS) of an affected Beagle, Drögemüller et al. (2014) identified ""a single-base-pair deletion at Chr2:19,796,293 compared with the CanFam 3.1 reference genome assembly . . . . The variant lies within exon 8 of the CUBN gene and represents a frameshift mutation leading to an early premature stop codon (c.786delC). The predicted protein from the mutant allele contains <10% of the amino acids from the wild-type CUBN (p.Asp262Glufs*47). Thus, the identified variant most likely represents a complete loss-of-function allele.""
Fyfe et al. (2014) reported the same c.786delC mutation in affected Beagles, as did Kook et al. (2014; J Vet Intern Med and J Small Anim Pract) in a single affected Beagle. " "Intestinal cobalamin malabsorption in Border Collies was mapped to CFA 2 in a genome wide association study (GWAS) using 7 cases and 7 controls. The best raw p-value in this analysis was 4.6E-6. The critical interval was defined by homozygosity mapping and spanned 3.53 Mb (Owczarek-Lipska et al. 2013).
Fyfe et al. (2013) conducted a genome scan on 19 Border Collies from families segregating for the disorder, using the Illumina 170K SNP chip. Homozygosity mapping highlighted a region on chromosome CFA2 centering on the CUBN gene." 9615
OMIA:001975 "Hanh et al. (2015) reported a likely causal allele as being ""a perfectly associated, single, non-synonymous coding variant in the canine tectonin beta-propeller repeat-containing protein 2 (TECPR2) gene affecting a highly conserved region was detected (c.4009C>T or p.R1337W)""." 9615
OMIA:001495 9615
OMIA:001828 "For eight of the nine haplotypes with a significant effect on calving rate (see Mapping section), Fritz et al. (2013) searched for causal mutations via whole-genome sequence data from 25 Holstein, 11 Montbéliarde and nine Normande bulls which had made major contributions to their breed. Specifically, they filtered ""for mutations that were (a) located at+or –6 Mb from the detected haplotype (b) carried in the heterozygous state by the carrier bulls and (c) absent from the non carrier bulls from the three breeds"" and then examined identified polymorphisms for their likely effect on protein structure and function. For MH2, Fritz et al. (2013) provided strong evidence for a candidate causal mutation, namely a nonsense mutation (g.28879810C>T; UMD 3.1 genome assembly) in the SLC37A2 gene (which solute carrier family 37, member 2), leading to p.R12X.
Reinartz and Distl (2016) reported homozygosity of this mutant in an aborted Vorderwald x Montbéliarde crossbred foetus inbred to Montbéliarde bulls. The mutant occurs at a frequency of around 5% in Vorderwald cattle with Montbéliarde ancestry but is absent from Vorderwald cattle with no Montbéliarde ancerstry." "By analysing Illumina Bovine 50k Beadchip genotype data from 47,878 Holstein, 16,833 Montbéliarde and 11,466 Normande cattle in the French genomic selection database, Fritz et al. (2013) identified 34 common (>1%) haplotypes that have a significant deficit (P<10^-4) of homozygotes in live animals, and which are, therefore, each likely to harbour a deleterious mutation. Three of these haplotypes, namely BY (Brachyspina; OMIA 000151-9913), HH1 (OMIA 000001-9913) and HH3 (OMIA 001824-9913), had been reported by VanRaden et al. (2011; J Dairy Sci 94:6153-61). Following the convention of naming such haplotypes with a first letter indicating breed, a second letter H for haplotype, followed by a sequential number, Fritz et al. (2013) named their 14 new Holstein haplotypes as HH4 to HH17, their 11 Montbéliarde haplotypes as MH1 to MH11, and their six Normande haplotypes as NH1 to NH6. Analyses of reproductive data indicated that nine of the 34 haplotypes have a significant effect on fertility, including six of the newly identified haplotypes, namely HH4, HH5, HH6, MH1, MH2 and NH5.
This present OMIA entry is for MH2, which is located in chromosome BTA29, at 27.9–29.1Mb (UMD 3.1 genome assembly) (Fritz et al., 2013)." 9913
OMIA:000162 "By sequencing a positional candidate gene in the both the TO-2 strain and the BIO14.6 strain (see OMIA 000515-10036), Sakamoto et al. (1997) identified a causal mutation that appears to be the same as that discovered in the BIO14.6 strain by Nigro et al. (1997) (see OMIA 000515-10036): ""A breakpoint causing genomic deletion was found to be located at 6.1 kb 5′ upstream of the second exon of δ-SG gene, and its 5′ upstream region of more than 27.4 kb, including the authentic first exon of δ-SG gene, was deleted. This deletion included the major transcription initiation site, resulting in a deficiency of δ-SG transcripts with the consequent loss of δ-SG protein in all the CM hamsters"". " 10036
OMIA:001263 "Sequencing of three candidate genes in the mapped region (see Mapping section above) enabled Cook et al. (2008) to identify a causal mutation as the substitution of ""C to a G at base 76 of exon 2 (c.188C>G)"" of the SLC36A1 gene, resulting in the amino-acid substitution T63R. " From a genome scan with 102 microsatellites, Cook et al. (2008) mapped this trait to a 6 cM region on chromosome ECA14. 9796
OMIA:001461 GM2 gangliosidosis, type I in Japanese Chin dogs is most likely caused by the c.967G>A variant in the HEXA gene, which leads to the p.E323K substitution. The wildtype glutamate at position 323 is part of the catalytically active site of hexosaminidase, Therefore, the variant is predicted to result in a complete loss of enzymatic activity (Sanders et al. 2013). Genotyping one of the two cases in this same breed for the c.967G>A variant provided supporting evidence for the causality of this variant (Freeman et al., 2013). The causative variant was identified by a candidate gene approach. 9615
OMIA:000689 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous disorder in humans and mice), Pierce et al. (2001) identified a causal mutation as a ""a cytidine to adenine transversion at position 156 of the Glra1 gene (156C>A). The 156A allele is predicted to substitute a termination codon for a tyrosine codon (Y24*) in exon 2 . . . This substitution is predicted to result in a prematurely truncated protein that lacks ligand-binding and membrane-spanning domains"". " 9913
OMIA:002107 "Lassoued et al. (2017): the likely causal variant is ""a composite polymorphism associating a single nucleotide substitution (c.301G > T), a 3 bp deletion (c.302_304delCTA) and a C insertion (c.310insC) in the ovine BMP15 cDNA leading to a frame shift at protein position 101""." 9940
OMIA:000361 "By sequencing the most likely candidate gene (based on a prolonged prothrombin time in the presence of a normal partial thromboplastin time) in a single Asian elephant, Lynch et al. (2017) identified the likely causal mutation as ""a single homozygous point mutation (c.202A.G) in the F7 gene of the FVII deficient elephant that was not present in unrelated elephants. This mutation causes an amino acid substitution (p.Arg68Gly) that is predicted to be deleterious.""" 9783
OMIA:001344 Building on the strong evidence from mapping (see Mapping section above), Mariat et al. (2003) identified a missense G457A transition in the equine MATP gene (now called SLC45A2), giving rise to a D153N amino acid substitution in cream horses. Mariat et al. (2003) showed that the candidate gene MATP is completely linked (theta = 0) to the equine cream locus. 9796
OMIA:001652 """A single nucleotide polymorphism (SNP) was identified at the first nucleotide of KIT intron 17 in the platinum fox. In platinum foxes, the A allele of the SNP disrupts the donor splice site and causes exon 17, which is part of a segment that encodes a conserved tyrosine kinase domain, to be skipped"" (Johnson et al., 2015)" 9627
OMIA:001523 The causative mutation is a 1,267 bp deletion that eliminates part of the 5’UTR, all of exon 1 and part of intron 1, which likely causes mRNA degradation and absence of COL9A2 protein (Goldstein et al., 2010). CFA15 9615
OMIA:001416 Anderson et a. (2009) showed that the 3bp deletion of the CBD103 gene that causes dominant black in dogs, exists also in the orthologous gene in wolves and coyotes, and is strongly associated with black coat colour in both these species. 9614
OMIA:002036 Charlier et al. (2016): nonsense (stop-gain) p.Arg527∗ 9913
OMIA:001515 9615
OMIA:000625 10141
OMIA:001058 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Rieger et al. (1998) showed the molecular basis for this disorder in Dutch Kooiker dogs to be a frameshift mutation in the gene encoding von Willebrand factor. Specifically, a G>A base substition at the first position of the donor splice site sequence of intron 16 results in a transcript containing 46 bases of intron, and creates a stop codon at amino acid position 729.
Venta et al. (2000) reported ""a single base deletion in the codon for amino acid 85 of the prepro-vWF cDNA"" as a causal mutation in Scottish Terriers.
As reported by Boudreaux (2012), a causal mutation in the Shetland Sheepdog breed was reported in US Patent 6074832 by Brewer et al. (Michigan State University) in 2000. To FN's knowledge, this discovery has not been published in the peer-reviewed literature. If anyone knows of a relevant publication, please contact FN." 9615
OMIA:000975 "Following the comparative candidate gene strategy, based on similar phenotypes in mice and dogs known to be due to mutations in the T gene that encodes Brachyury (a transcription factor which regulates notochord differentiation), Buckingham et al. (2013) characterised and ""sequenced the T gene in several independent lineages of Manx cats from both the US and the Isle of Man and identified three 1-bp deletions [c.998delT; c.1169delC; c.1199delC] and one duplication/deletion [c.998_1014dup17delGCC], each predicted to cause a frameshift that leads to premature termination and truncation of the carboxy terminal end of the Brachyury protein"". Buckingham et al. (2013) went on to report ""No evidence suggested that the presence of a specific mutant allele of T determined the extent of tail length reduction in the Manx cat . . . no cats were homozygous or compound heterozygous for mutations in T, supporting complete absence of Brachyury results in early embryonic lethality. Genotyping of three fetal cats that died late in gestation found that in all three instances, these individuals were heterozygous for mutant T alleles.""" After identifying the four causal mutants in the T gene (see Molecular basis section), Buckingham et al. (2013) conducted a linkage analysis between the T gene and the short-tail trait, and showed zero recombination. 9685
OMIA:001483 "Drögemüller et al. (2009) showed that this disorder in Dachsunds is due to a missense variant (c.977T>C, p.Leu326Pro) in a conserved domain of the SERPINH1 gene. SERPINH1 acts as a chaperone to assist in the correct assembly of the nascent procollagen chains (Widmer et al. 2012). Lindert et al. (2015) investigated the functional impact of the SERPINH1 variant in detail by studying fibroblast cultures from affected and non-affected Dachshunds. The researchers found that ""procollagen was retained intracellularly with concomitant dilation of ER cisternae and activation of the ER stress response markers GRP78 and phospho-eIF2α, thus suggesting a defect in procollagen processing."" They further observed post-translational over-modification and abnormal cross-linking of the bone collagen." By using homozygosity mapping in only 5 affected dogs, Drögemüller et al. (2009) narrowed the location of the causative mutation down to a 5.82 Mb region in chromosome CFA21. 9615
OMIA:001798 "Following the results described in the Mapping section, sequencing of BMP15 revealed six polymorphisms, one of which (950C>T; T317I) was strongly associated with fecundity. Genotyping of this polymorphism in additional randomly chosen ewes confirmed the effect, with TT homozygotes having an average ovulation rate of 4.58 compared with 2.94 for CT and 2.53 for CC ewes, with corresponding averages for litter size being 2.50 for TT, 1.93 for CT and 1.83 for CC (Demars et al., 2013). Interestingly, the authors note that the high fecundity of homozygous mutant (TT) ewes is ""in striking contrast with the sterility exhibited by all other known homozygous BMP15 mutations""." Demars et al. (2013) conducted a GWAS by genotyping 28 hyper-prolific and 11 control French Grivette ewes with the Illumina OvineSNP50 chip. A single region on the X chromosome, including the prolificacy gene BMP15, was highlighted. BMP15 was thus a highly likely positional candidate gene. 9940
OMIA:002077 "Jia et al. (2016): ""a 54-bp insertion mutation in the upstream region of miR-15a-16 . . . resulted in lower miR-16 expression by introducing three novel splicing sites instead of the missing 5′ terminal splicing of mature miR-16. Elevating miR-16 significantly inhibited DF-1 chicken embryo cell proliferation, consistent with a role in suppression of cellular growth."" " 9031
OMIA:001737 "Whole-genome sequencing of ""One spotted and eight solid camels"" enabled Holl et al. (2017) to report that the ""spotted camel was heterozygous for a frameshift deletion in KIT (c.1842delG, named KITW1 for White spotting 1), whereas all other camels were wild-type (KIT+/KIT+). . . . The frameshift results in a premature stop codon five amino acids downstream, thus terminating KIT at the tyrosine kinase domain. . . . p.M614IfsX5"" These authors also reported that ""No additional mutations unique to the spotted camel were detected in the EDNRB, EDN3, SOX10, KITLG, PDGFRA, MITF, and PAX3 candidate white spotting genes"". They also reported that a different type of white spotting is likely to be due to another variant." 9838
OMIA:001936 "As reported by Murgiano et al. (2014), the candidate region (mentioned in the Mapping section above) contains 42 annotated and several uncharacterised genes, none of which are obvious functional candidate genes for this disorder. Analysis of whole-genome sequencing data from of one of the affected calves (~x13.5) and 44 other cattle from 15 breeds narrowed the field of positional candidate causal mutations down to one SNV in an uncharacterised gene and ""an 855 bp deletion across the exon 19/intron 19 border of the bovine nidogen 1 (NID1) gene (c.3579_3604+829del)"". Genotyping of a larger cohort confirmed the deletion as being causal. Murgiano et al. (2014) also reported that ""RT-PCR showed that NID1 is expressed in bovine lenses while the transcript of the second locus was absent. The NID1 deletion leads to the skipping of exon 19 during transcription and is therefore predicted to cause a frameshift and premature stop codon (p.1164fs27X). The truncated protein lacks a C-terminal domain essential for binding with matrix assembly complexes.""" "Murgiano et al. (2014) genotyped 4 affected half-sib calves, their 4 dams and their sire with the Illumina BovineHD BeadChip, and gathered comparable SNP genotype data from 51 other Romagnolas. A GWAS with 549,341 informative SNPs mapped the disorder to a ""single contiguous genomic region (3.32–10.05 Mb) on bovine chromosome 28 (BTA 28)"" which was confirmed by homozygosity mapping." 9913
OMIA:001934 "Comparison of sequence of the 713kb candidate region (mentioned in the mapping section above) in an obligate carrier, one of its offspring, 43 members of the Fleckvieh breed (in which the disorder has never been reported) and 191 non-Fleckviehs from the 1000-bulls project revealed 2 candidate causal SNVs: a coding variant and an intronic variant of the gene UBE3B, which encodes ubiquitin protein ligase E3B, and mutations in which cause a similar syndrome in humans (see MIM links above). Sequencing of animals in other families in which the disorder segregates pointed to the coding variant (rs475678587G>A; p.E692E; Chr17:65,921,497 bp) as being causal. This synonymous variant occurs at the very last nucleotide of exon 23, at the junction with intron 23, resulting in skipping of the entire exon 23. As reported by Venhoranta et al. (2014), this results ""in an altered protein lacking 40 amino acids, of which 20 are located in the conserved HECT-domain, the catalytic site of the UBE3B protein.""
In their table of reduced-fertility haplotypes, Cole et al. (2014) list this UBE3B mutation as being causal for the infertility effect of haplotyoe AH1." "By conducting a GWAS on 9 affected and 37 normal half-sibs, each genotyped with the Illumina BovineHD Bead chip (yielding 623,881 informative SNPs), Venhoranta et al. (2014) mapped this disorder to a region between 65,659,074 bp and 65,981,740 bp (UMD3.1 assembly) on chromosome BTA17. Subsequent homozygosity mapping reduced the candidate region to 713 kb (65,645,831 bp - 66,358,629 bp), which contains 14 genes.
Using a strategy similar to that of VanRaden et al. (2011), Cooper et al. (2014) discovered a ""haplotype [which they named AH1] that affects Aryshire fertility . . . on Bos Taurus chromosome 17 in the range 65.9 to 66.2"". " 9913
OMIA:000119 "Bighignoli et al. (2007) reported haplotypes within the CMAH gene that correspond with the A and b alleles of this blood group system. The haplotypes are characterised by six mutations: ""2 SNPs upstream of the start, an indel in the exon 1 5' UTR and three missense mutations in the coding region"".
Gandolfi et al. (2016): ""A novel variant [in CMAH], c.364C>T, was identified that is highly associated with blood type AB in Ragdoll cats and, to a lesser degree, with type AB in random bred cats""
Two new variants (c.179G>T and c.187A>G) were reported by Omi et al. (2016)." 9685
OMIA:001545 Brown coat colour is associated with a small deletion: c.50_52del; p.Leu18del (Zhang et al., 2014) 30521
OMIA:001176 By cloning and sequencing a very likely comparative candidate gene (based on homologous clinical signs in other species), Nezamzadeh et al. (2005) identified the causative mutation of this disorder in a family of German Blackface sheep as a missense base substitution (C>T) in the UROD gene, resulting in L131P at the active cleft site of the peptide. 9940
OMIA:000626 By cloning and sequencing a very likely comparative candidate gene (based on the homologous human and bovine disorder), Leipprandt et al. (1996) detected a single base deletion in the caprine MANBA (mannosidase, beta A, lysosomal) gene, resulting in a frameshift and hence premature termination, yielding a deduced peptide of 481 amino acids, compared to the normal peptide of 879 amino acids. The authors designed a PCR genotyping test which they used with success to distinguish the three genotypes at this locus. 9925
OMIA:001106 "Drögemüller et al. (2011) identified a likely causal variant in Tyrolean Grey cattle as the synonymous c.2229C>T SNP, which ""is located within a putative exonic splice enhancer (ESE) and the variant allele leads to partial retention of the entire intron 19 and a premature stop codon in the aberrant MFN2 transcript. Thus we have identified a highly unusual splicing defect, where an exonic single base exchange leads to the retention of the preceding intron.""" 9913
OMIA:000317 "Among the 64 genes in the mapped region (see Mapping section), Koch et al. (2013) reported that HMX1 (which encodes a transcription factor) stood out as a ""striking functional [comparative] candidate"" (based on known mutations in humans, mice and rats). Whole-genome sequencing of a severely affected cow (assumed to be homozygous) revealed ""6 non-synonymous DNA variants within the two coding exons of HMX1 and two structural variants within the downstream highly conserved region"". Genotyping by sequencing in other animals excluded all but one of the structural variants, namely a 76bp duplication (Copy Number Variant; CNV), which was confirmed as the causal mutation by subsequent genotyping in 40 affecteds and 80 control Highland cattle, as well as in 144 cattle from a range of other breeds. As reported by Koch et al. (2013), ""The affected ultra-conserved enhancer is located 148 kb apart of the coding region of HMX1 . . . . The sequence of the 76 bp duplication is highly conserved . . . . In silico prediction revealed several transcription factor binding sites indicating the potential functional relevance of this region""." From a GWAS on 32 affected and 36 control Highland cattle, each genotyped with the Illumina bovine HD SNP chip (yielding 519,828 informative SNPs), Koch et al. (2013) mapped this trait to a 4Mb region of chromosome BTA6 (106Mb to 110Mb; UMD3 assembly). 9913
OMIA:000944 "Westaway et al. (1994) cloned and sequenced the sheep PrP locus, and provided strong evidence that homozygosity for an allele with the coding-strand triplet CAG(Gly; Q) at codon 171 ""is necessary but not sufficient for the development of natural scrapie""." 9940
OMIA:001920 In the course of sequencing the GHRH gene in largemouth bass, Ma et al. (2014) identified a 66bp deletion (c.-923_-858del) in the 5' flanking region of the GHRH gene, and via segregation studies, showed that it is an autosomal recessive embryonic lethal. The heterozygote does not differ significantly from the normal homozygote in growth traits. 27706
OMIA:000526 "After sequencing the most obvious candidate gene in the candidate region (see Mapping section) and discovering no mutations, Pemberton et al. (2014) sequenced all 199 exons of the remaining 16 genes in that region, yielding 54 variants, only one of which had the potential to be deleterious. This variant turned out to be the causal mutation: ""a deletion of a single A nucleotide within exon 9 of the gene encoding folliculin-interacting protein 2 (FNIP2). This mutation at nucleotide 880 of the coding sequence (c.880delA, XM_532705) causes a frameshift, and the amino acid sequence is altered beginning at codon 294, with a premature translation stop signal introduced at codon 296 . . . . A highly truncated protein of 295 amino acids compared with the wild-type protein of 1,106 amino acids is predicted to result from this p.Ile294fsX296 mutation""" "By conducting a GWAS on 84 Weimaraner dogs ""(40 males and 44 females) of whom 14 were affecteds, 19 were known carriers, and 51 were unaffecteds"", each genotyped with the Illumina CanineHD BeadChip (yielding 95,990 informative autosomal SNPs), Pemberton et al. (2014) mapped this disorder to a 5Mb region (57.3 to 62.3) on chromosome CFA15. Subsequent homozygosity mapping narrowed this to a 3.7Mb region (573. to 61.0)." 9615
OMIA:001680 "Philipp et al. (2011) reported the cause of this disorder as being a ""missense mutation (c.629G>T, p.210R>I) was identified within exon 7 of the bovine MITF"" gene. " "Using a genome-wide scan with the bovine Illumina SNP chip, Philipp et al. (2011) mapped this disorder to a region of chromosome BTA22 identified by three SNPs located ""at 33.422, 36.052 and 36.060 Mb"". This regions contains 13 genes, including the gene encoding microphthalmia-associated transcription factor (MITF), a strong candidate." 9913
OMIA:001504 "A causative mutation in Dachshunds is a single nucleotide insertion (c.736-737insC) in exon 8 of PPT1, which causes a frameshift in amino acid codons and a premature stop codon. The resultant truncated PPT1 protein lacks a hydrophobic region that is key to enzyme activity, such that the affected dachshund brain has only 3% activity of normal dogs (Sanders et al., 2010).
Whole-genome sequencing of an affected Cane Corso dog by Kolicheski et al. (2016) revealed the likely causal variant to be ""a PPT1c.124 + 1G>A splice donor mutation. This nonreference assembly allele was homozygous in the affected dog, has not previously been reported in dbSNP, and was absent from the whole genome sequences of 45 control dogs and 31 unaffected Cane Corsos."" " CFA15 9615
OMIA:002037 Charlier et al. (2016): missense p.Tyr195Cys 9913
OMIA:000667 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous disorder in humans and other mammals), Ray et al. (1998; Genomics 48:248-253) identified the initial causative mutation as a ""guanosine to adenine base change at nucleotide position 559 in the canine cDNA sequence [that] causes an arginine to histidine substitution at amino acid position 166"" of the gene coding for hydrolase beta-glucuronidase (GUSB).
In Brazilian Terriers, Hytönen et al. (2012) sequenced the entire 13Mb candidate region from their GWAS (see Mapping section), and discovered that the disorder in this breed is due to a ""missense mutation (c.866C>T) causing a pathogenic p.P289L change in a conserved functional domain of β-glucuronidase (GUSB)""." By conducting a GWAS on 7 affected and 11 control Brazilian Terriers, each genotyped with the Illumina’s 22K SNP chip (yielding 16,595 SNPs for analysis), Hytönen et al. (2012) highlighted a region on chromosome CFA6. Subsequent homozygosity mapping narrowed the region to 13Mb, including more than 200 genes. [FN; 20 May 2013] 9615
OMIA:001819 "Cloning and sequencing of the bovine gene encoding molybdopterin cofactor sulfurase (MCSU, now called MOCOS) in normal and affected cattle, by Watanabe et al. (2000), revealed the causal mutation to be a 3bp deletion (c.769_771delTAC) of codon 257 (deleting Tyr) in the MOCOS gene.
Murgiano et al. (2016) discovered a different mutation in the MUCOS gene as the likely cause in Tyrolean Grey cattle: ""1 bp deletion in the molybdenum cofactor sulfurase (MOCOS) gene (g.21222030delC; c.1881delG and c.1782delG), located in an 11 Mb region of homozygosity on BTA 24)""." "By conducting a genome scan on 21 affected offspring and their parents (21 dams and two sires), each genotyped with 200 microsatellites, Watanabe et al. (2000) linkage-mapped this disorder to the ""centromeric region of bovine chromosome (BTA) 24"". They then FISH-mapped the most likely comparative candidate gene (based on the most likely causative gene in humans), namely Drosophila ma-l orthologue (encoding the putative molybdopterin cofactor sulfurase, which is required for normal activity of both XDH and AO; see Clinical section), to ""BTA24q13.1–13.3"", which corresponds to the linkage-mapped location of the disorder locus." 9913
OMIA:002080 Based on clinical signs and detailed diagnostic tests, Maudlin et al. (2016) sequenced the most likely candidate gene (PLEC) in all six members of a litter of Eurasier dogs, comprising three affecteds (two females and one male) and three normals, plus the two normal parents. They discovered a nonsense SNP (CanFam3 chr13: g.37461941G>A; c.?G>A; p.Trp?Stop) that segregates perfectly with the disorder and which is absent in 25 dogs of each of five other breeds. 9615
OMIA:001101 9031
OMIA:001553 The causative mutation for cmr2 in the Coton de Tulear is a G to A missense mutation in BEST1 (Guziewicz et al., 2007). CFA18 9615
OMIA:000256 "Mizukami et al. (2014): a ""missense mutation (c.1342C>T) ... [resulting] in a deleterious amino acid substitution (p.Arg448Trp) of a highly conserved arginine residue in the rBAT protein encoded by the SLC3A1 gene""." 9685
OMIA:000366 Burgstaller et al. (2016) have provided strong evidence that the FH2 frameshift mutation (see OMIA 001958-9913), namely c.771_778delTTGAAAAGinsCATC (rs379675307) in SLC2A2, is actually causative of Fanconi-Bickel syndrome in Fleckvieh cattle. 9913
OMIA:000031 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous phenotype in humans and mice), namely MLPH, Drögemüller et al. (2007) identified a causal mutation as an ""an A/G SNP located at the last nucleotide of the untranslated exon 1 (c.-22G>A)"" which ""affects a conserved nucleotide of the splice donor recognition motif"". As a result of the ""reduction of splicing efficiency"", the authors reported that ""the mutant A-allele is predicted to reduce splicing efficiency 8-fold""." Philipp et al. (2005) mapped a very likely comparative candidate gene (based on a similar dilute mutant in mice, namely Mlph), to canine chromosome CFA25q24. 9615
OMIA:001561 "Olsson et al. (2011), from the LUPA consortium, presented evidence suggestive that the ""distinctive thick and heavily folded skin"" of the Shar-Pei breed is associated with several copies of a the ""meatmouth"" (CNV-E) duplication upstream of the HAS2 gene that encodes hyaluronic acid synthase 2. The duplication results in over-expression of the HAS2 enzyme which in turn results in a build-up of hyaluronan (HA) in the skin, creating the breed-specific characteristic. Unfortunately, a build-up of HA also increases the risk of periodic fever syndrome, by triggering the innate immune response.
Metzger and Distl (2014) reported no difference in the number of copies of either the ""meatmouth"" or ""traditional"" duplications between 16 ""susceptible"" and 79 ""unaffected"" Shar-Pei dogs.
Using droplet digital PCR (ddPCR), Olsson et al. (2016) showed that alleles of CNV_14.3 and CNV_16.1 remain stable between generations (i.e. the number of copies remains stable). The also showed that ""CNV_16.1 allele five (CNV_16.1|5) resulted in a four-fold increase in the odds for SPAID (p A; c.??G>A; p.E??K] acting via MDM2 [Mouse double minute 2 homolog] for a proinflammatory reaction"" ""to be highly associated with SPAID in Shar-Pei""." "By genotyping 39 affected and 17 control Shar-Pei dogs with either the ""27K (v1) and 50K (v2) canine Affymetrix SNP chips"" (yielding 17,227 informative SNPs for analysis), Olssen et al. (2011) showed that a region of canine chomosome CFA13 is the likely site of a selective sweep in the Shar-Pei breed, reflecting selection for the breed-defining thickened, folded skin. By conducting a GWAS on the same data, they also showed that this same region of CFA13 has the strongest association with susceptibility to Familial Shar-Pei fever. Resquencing in this region of CFA13 revealed two duplications upstream of the HAS2 (hyaluronic acid synthase 2) gene: ""The “meatmouth” duplication was the larger fragment, 16.1 Kb (CanFam 2.0 Chr13: 23,746,089–23,762,189) with breakpoints located in repeats (a SINE at the centromeric end and a LINE at the telomeric end) and individual copies separated by seven base pairs. . . . [and] The “traditional” duplication was 14.3 Kb (CanFam 2.0 Chr13: 23,743,906–23,758,214)""
In a GWAS on 255 Shar-Pei, comprising five overlapping case subsets (fever, arthritis, vesicular hyaluronosis, otitis and amyloidosis) and three overlapping control subsets, each genotyped with the Illumina Canine 170 K SNP chip (yielding between 106,298 and 111,880 informative SNPs), Olsson et al. (2013) revealed a major QTL for all five subsets of the disorder on chromosome CFA13, between 21.5Mb and 28.3Mb (CanFam 2.0). For one of the subsets (amyloidosis), a modifer QTL was identified on CFA14 ""at approximately 39 Mb and 55 Mb""." 9615
OMIA:000211 "Sequencing of a very likely comparative positional candidate gene (SILV or PMEL17; now known as PMEL) (see Mapping section above) in Shetland Sheedogs of the three merle genotypes by Clark et al. (2006) revealed ""an insertion of a tRNA-derived SINE . . . . The insertion occurs at the boundary of intron 10 and exon 11 and is flanked by a 15-bp target site duplication . . . . The SINE insertion is in reverse orientation, with the 5′ end closer to exon 11.""
Having noticed in a mixed-breed non-merle dog some ophthalmologic abnormalities similar to those seen in merle dogs, Imamoto et al. (2011) discovered that this mixed-breed dog was actually carrying the above SINE-insertion PMEL merle mutation, and was therefore a cryptic merle. " "Using a genome scan with the ""multiplexed Minimal Screening Set 2"" of 327 canine microsatellites genotyped on 9 merle and 32 non-merle Shetland Sheepdogs, Clark et al. (2006) LD-mapped the merle locus to a single marker (FH2537) on chromosome CFA10. A search of homologous regions in the genomes of humans and mice revealed the SILV gene as a comparative positional candidate." 9615
OMIA:000979 "Davey et al. (2006) identified the talpid-3 gene as being KIAA0586, and showed that the mutant allele is the result of the insertion of a single T creating a frameshift which ""is predicted to produce a truncated protein of 366 amino acids compared with 1524 in wild type ""." 9031
OMIA:002041 Charlier et al. (2016): splice-site c.826+1G>A 9913
OMIA:000884 "Having observed substantial suppression of recombination in the vicinity of the mapped Rose-comb locus on chromosome GGA7, Imsland et al. (2012) suspected that the trait could be associated with an inversion. Genomic resequencing subsequently confirmed ""a 7.38 Mb inversion with breakpoints located approximately at 16.50 Mb and 23.88 Mb"". The Rose-comb phenotype arises because the inversion results in ""the relocalization of the MNR2 homeodomain protein gene leading to transient ectopic expression of MNR2 during comb development"". Naming this Rose-comb allele R1, Imsland et al. (2012) also report a second Rose-comb allele (R2), which ""must have originated by a recombination event between the wild-type allele at position 16.50 Mb and the R1 allele at position 23.79 Mb in the inverted region . . . . The consequence of this recombination event is that R2 does not carry the entire inversion but instead has two duplicated segments, one 91 kb fragment (23,790,414–23,881,384 bp) that represents a remaining fragment of the inverted region together with a small duplicated fragment of 198 bp (16,499,583–16,499,781 bp) that is present on both sides of the 91 kb duplication"". The same authors also were able to provide a molecular explanation for the very first example of epistasis (interaction between genes) ever reported (by Bateson and Punnett, 1908), namely the walnut comb, which results from the combined action of Rose-comb and Pea-comb alleles (see OMIA 000782-9031): ""Transient ectopic expression of MNR2 and SOX5 (causing the Pea-comb phenotype) occurs in the same population of mesenchymal cells and with at least partially overlapping expression in individual cells in the comb primordium"". Finally, Imsland et al. (2012) were also able to provide an explanation for the well-documented pleiotropic effect of Rose-comb, namely that male homozygotes have poor sperm motility (see Crawford and Merritt, 1963, and many more recent references in the list below). The authors propose that this pleiotropy arises from the inversion breakpoint of allele R1 coinciding with a gene (CCDC108) whose encoded peptide includes a major sperm protein domain. " The linkage group to which this locus belongs became known as linkage group II, which was later shown to be located on chromosome GGA7 (Vaez et al., 2008). A GGA7 location was confirmed by Dorshorst et al. (2010), the most likely region being 16.9–22.4 Mb. 9031
OMIA:000187 "By sequencing within BAC and YAC contigs covering the candidate region of BTA6, Takeda et al. (2002) identified a new coding sequence containing two mutations that each co-segregate with the disorder in Japanese Brown cattle, namely:
""a C to T transition at position 1356 (C1356T) . . . Remarkably, the C1356T mutation created a cryptic splice donor site in exon 11 (AAGGT1356GAGC) that substituted for the authentic splice donor site and led to improper splicing at position 1355, resulting in the 56-base RNA deletion between 1355 and 1410""; and
""a CA to G substitution at position 2054–2055 (2054–2055delCAinsG) . . . The substitution also caused a frameshift and a premature termination at codon 706, resulting in a 42% shortened protein"".
The authors showed clearly that each of these mutations cause the disorder in this breed, i.e. affected calves can be homozygous for either mutant allele or heterozygous for the two mutants.
Takeda et al. (2002) called the newly-identified gene LIMBIN (symbol LBN) because of its association with abnormal limb development. This gene is now called EVC2, because subsequent research suggests that it arose by duplication of the immediately adjacent EVC gene. As explained in the OMIM entry (above), mutations in human EVC and EVC2 cause a similar type of dwarfism in humans [FN 10th Nov 2005; Mohammad Shariflou 7/11/2006; FN 21 Sep 2012]
By whole-genome sequencing of one affected Tyrolean Grey calf, and study of potential missense variants in the candidate region, Murgiano et al. (2014) identified the causal mutation to be ""a 2 bp deletion located in exon 19 of the bovine EVC2 gene (c.2993ACdel) . . . The mutation is predicted to cause a frameshift and premature stop codon beginning with amino acid residue 998 in the bovine EVC2 protein sequence (p.Asp998GlufsTer13)"". Sanger sequencing and genotyping of other animals in segregating families confirmed this as the causal mutation in this breed." "This locus was linkage mapped to the distal end of BTA6 in Japanese Brown cattle by Yoneda et al. (1999). Takeda et al. (2002) refined the region to approximately 2 cM.
By conducting a GWAS on 31,045 informative SNPs genotyped in each of 7 affected and 44 normal Tyrolean Grey cattle, and subsequent homozygosity mapping, Murgiano et al. (2014) mapped this disorder to a 1.6Mb region on chromosome BTA6 that is coincident with the map location in Japanese Brown cattle." 9913
OMIA:001972 "Imsland et al. (2016) showed that ""pigment dilution in Dun horses is due to radially asymmetric deposition of pigment in the growing hair caused by localized expression of the T-box 3 (TBX3) transcription factor in hair follicles, which in turn determines the distribution of hair follicle melanocytes."" In contrast, ""Most domestic horses are non-dun, a more intensely pigmented phenotype caused by regulatory mutations impairing TBX3 expression in the hair follicle, resulting in a more circumferential distribution of melanocytes and pigment granules in individual hairs"" (Imsland et al., 2016). These same authors ""identified two different alleles (non-dun1 and non-dun2) causing non-dun color. non-dun2 is a recently derived allele, whereas the Dun and non-dun1 alleles are found in ancient horse DNA, demonstrating that this polymorphism predates horse domestication"" and concluded ""These findings uncover a new developmental role for T-box genes and new aspects of hair follicle biology and pigmentation""." "Imsland et al. (2016) ""mapped the Dun locus to a region on horse chromosome 8 (chr. 8: 18,061,745–18,482,196) using microsatellite markers and then fine-mapped the locus with a 27-SNP panel to a 200-kb region containing only one gene, TBX3""" 9796
OMIA:001009 "Deletion: around 45,694 bp including exon 1 of ALX4 of Shorthorns (Beever and Marron, 2012)
Duplication: 20bp duplication in exon 2 of ALX4 of Galloways; g.75154399_75154418dup (AC_000172; UMD3.1), creating a frameshift (Brenig et al., 2015)" Chromosome BTA15 9913
OMIA:001758 "Building on their mapping results (see above), Mellersh et al. (2006) sequenced the HSF4 gene in Staffordshire Bull Terriers segregating the disorder, and identified ""a single C nucleotide insertion in exon 9 (CFA5 g85286582–85286583insC) that alters the reading frame of the gene and introduces a premature stop codon"". The same mutation appears to be causative in Boston Terriers, and a different mutation in the same gene appears to be causative in Australian Shepherds: ""a deletion of a C nucleotide at the same position of exon 9 in the affected Australian Shepherds (in which the disorder is autosomal dominant, unlike in the other two breeds, where it is autosomal recessive) (g.85286582delC) . . . , which is also predicted to alter the frame of the gene and introduce a premature stop codon, 177 nucleotides (59 amino acids) further downstream from that introduced by the deletion"". Finally, the authors showed that neither of these mutations is causative in American Cocker Spaniels and Golden Retrievers. The following year, Mellersh et al. (2007) showed that late-onset cataract in Boston Terriers is not due to any mutation in HSF4. Engelhardt et al. (2007) showed that HSF4 mutations are not causative for primary cataract in English Cocker Spaniels and Wire-haired Kromfohrlanders. Müller et al. (2008) drew the same conclusion for primary cataract in Dachshunds and Entlebucher Mountain dogs. Mellersh et al. (2009) confirmed the Australian Shepherd mutation but also reported that other mutations are also likely to be involved." "Using sequence data from the initial canine genome assembly (Lindblad-Toh K, Wade CM, Mikkelsen TS et al. Nature 2005; 438: 803–819), Mellersch et al. (2006) identified microsatellite markers ""adjacent to and flanking"" each of 20 comparative candidate genes (based on known causative mutations in humans and mice). Association analysis with this disorder was conducted within each of the breeds Staffordshire Bull Terriers, American Cocker Spaniels, Golden Retrievers and Miniature Schnauzers. The only association was with markers flanking the gene HSF4 on chromosome CFA5 in Staffordshire Bull Terriers.
Ricketts et al. (2015) mapped a second locus in Australian Shepherd dogs to a 14.16 Mb region on chromosome CFA13 at 46.4 Mb" 9615
OMIA:001405 By cloning and sequencing a set of likely candidate genes (based on knowledge of the physiology of this type of metabolism) Mise et al. (2004; Pharmacogenetics 14:769-73) showed that a 1117C>T nonsense mutation in the CYP1A2 gene is associated with the poor metabolizer (PM) phenotype in relation to AC-3933. The same mutation was reported by Tenmizu et al. (2004) as being associated with the PM phenotype in relation to YM-64227. 9615
OMIA:000621 "The molecular basis of MH in pigs was discovered via identification of a strong candidate gene, namely RYR1, that encodes a calcium release channel of skeletal muscle sarcoplasmic reticulum. When it was shown that this candidate gene mapped very closely to MH in pigs and in humans, the race was on to clone and sequence the RYR1 gene. The race was won by a Canadian research team led by David MacLennan (Fujii et al., 1991) who showed that MH is due to a base substitution (C-T) in the 1843rd nucleotide of the RYR1 gene. The base substitution causes an amino-acid substitution (arginine - cysteine) in the 615th position of the calcium release channel, resulting in altered calcium flow. It is remarkable that the smallest possible change (a single base-substitution) leading to a single amino-acid-substitution in a very large molecule (comprising 5,035 amino acids) can have caused a disorder that was a major financial burden for the global pig industry for several decades.
Interestingly, Bates et al. (2012) reported that ""A proportion of pigs normal for RYR1 did exhibit limb rigidity during halothane gas challenge, and subsequently tended to have lower 45 min pH and greater longissimus muscle fluid loss post harvest."" This suggests that the RYR1 locus is not the only factor determining reaction to halothane." Building on reports of association between halothane-induced malignant hyperthermia (Hal) and various gene markers, Andresen and Jensen (1977) showed that Hal is linked to the gene encoding phosphohexose isomerase (PHI), now called glucose phosphate isomerase (GPI). By the mid-1980s, this linkage group had been expanded to comprise six loci, including Hal (Archibald and Imlah, 1985). Using in situ hybridisation of a clone containing the porcine GPI gene, Davies et al. (1988) showed that the Hal linkage group maps to chromosome SSC6p12-q22. Also using in situ hybridisation, Harbitz et al. (1990) physically mapped the RYR1 gene (then called the calcium release channel [CRC] gene) to chromosome SSC6p11-q21. 9825
OMIA:001200 "The discovery by Meredith et al. (2005; Am. J. Hum. Genet. 75: 703-708) that the molecular basis of human MPD1 is a range of mutations in the myosin heavy-chain gene (MYH7), suggested a strong comparative candidate gene for Campus syndrome. When the porcine genome assembly became available, Murgiano et al. (2012) checked that the porcine MHY7 gene is located in the Campus region and then, by sequencing affected animals, identified ""an in-frame insertion within exon 30 of MYH7 (c.4320_4321insCCCGCC) which was perfectly associated with the disease phenotype. . . . The mutation is predicted to insert two amino acids (p.Ala1440_Ala1441insProAla) in a very highly conserved region of the myosin tail.""" In an abstract, Tammen and Harlizius (1996) reported having mapped Campus syndrome to chromosome SSC7q. Tammen et al. (1999) reported the details of this mapping, involving a genome scan with 254 microsatellites thta located the Campus gene in a 8cM region of SSC7q. Tammen et al. (1999) noted that this region of SSC7 corresponds to a portion of human chromosome HSA14 and that a human disorder homologous to Campus syndrome, namely dominant distal myopathy type 1 (MPD1), maps to this region of HSA14. 9825
OMIA:001334 "Pausch et al. (2016): ""a 1 bp deletion (Chr13: 24,301,425 bp, ss1815612719) in the eleventh exon of the armadillo repeat containing 3-encoding gene (ARMC3) that was compatible with the supposed recessive mode of inheritance. The deletion is expected to alter the reading frame and to induce premature translation termination (p.A451fs26). The mutated protein is shortened by 401 amino acids (46 %) and lacks domains that are likely essential for normal protein function.""" "Pausch et al. (2016): ""an 8.42 Mb segment on BTA13 (from 22,308,682 bp to 30,733,648 bp)""" 9913
OMIA:001506 "In one of the early uses of the initial canine genome assembly, Katz et al. (2005) conducted megablast searches of the canine genome with all eight then-known human genes for ceroid lipofuscinosos. One of these (CLN8) was shown to be located on CFA37, near to the mapped location of this disorder (see Mapping section above). Sequencing of the canine CLN8 gene in affected English Setters revealed the causative mutation to be ""a T-to-C transition in the CLN8 gene that predicts a p.L164P missense mutation"".
Whole-genome sequencing of an affected ""mixed breed dog with Australian Shepherd and Blue Heeler ancestry"" enabled Guo et al. (2014) to identify a nonsense mutation in the CLN8 gene of this dog, namely c.585G>A; p.Trp195*. Genotyping of archival samples enabled these authors to confirm the causality of this mutation.
Hirz et al. (2017) reported ""a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form observed in both cases"" ""of NCL in Alpenländische Dachsbracke dogs from different litters of the same sire with a different dam"".
" "Lingaas et al. (1998) conducted a genome scan with a panel of 103 microsatellites in a pedigree of ""133 animals in three families with a total of 117 offspring"". Subsequent genotyping of additional animals with a targetted set of markers from the genome scan enabled Lingaas et al. (1998) to report that ""Linkage analysis showed three genetic markers to be linked to the disease locus with the closest marker at a distance of about 3 CM. Two other loci were linked with these markers making a linkage group of five genetic markers. The linkage group spanned a distance of 54 CM."" At this time, this linkage group had not been allocated to a particular canine chromosome. By 2005, it was known that this linkage group corresponds to a region of chromosome CFA37 (Katz et al., 2005)." 9615
OMIA:000836 The report of the use of a DNA genotyping test by Healy et al. (1995), citing a personal communication from G.S. Johnson at the University of Missouri, implied that the molecular basis of this disorder within the gene for ferrochelatase had been determined by Dr Johnson. Jenkins et al. (1998) appear to have been the first to publicly report the molecular basis of this disorder. They did so by cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), and reported a base substitution in the stop codon of the bovine ferrochelatase gene, that destroys that codon, resulting in an additional 27 amino acids in the peptide. To FN's knowledge, this is the first reported case in non-laboratory animals of the obliteration of a stop codon by a base substitution: a stop-loss or extension mutation. 9913
OMIA:000017 Molecular evidence provided by Yang et al. (1993) implicates a large deletion in the gene for cholesterol side-chain cleavage enzyme (P450SCC, renamed CYP11A1). Sequencing of the normal and mutant forms should provide definitive evidence of the nature of the mutation. 9986
OMIA:002103 "Starting with a GWAS on genetically related polymelia affected and normal Angus calves under an assumption of recessive inheritance, Prof. Beever identified a likely causal mutation for this disorder in August 2013. The mutation was disclosed by Beever et al. (2014): a ""non-synonymous substitution was identified within exon 5 of the bovine NHL repeat containing 2 (NHLRC2) gene causing a valine to alanine substitution at residue 311 (V311A) of the encoded protein. Comparative analysis using the protein sequence from diverse taxa indicates the amino acid valine is invariable among the 53 species with sequence available.” (Text provided jointly by FN and Laurence Denholm)" 9913
OMIA:000754 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Campbell et al. (2000) showed that the disorder in a Golden Retriever was due to ""a G to C point mutation for nucleotide 1,276 [of the COL1A1 gene], predicting a codon change from glycine (GGA) to alanine (GCA) for amino acid 208. This change disrupts the normal Gly-X-Y pattern of the collagen triple helix.""" 9615
OMIA:001445 Minivielle et al. (2002) showed that this locus is orthologous to the lavender locus in chickens, which is encoded by the MLPH gene. Bed'hom et al. (2012) reported the causal mutation as being a large deletion in the region of the quail MLPH gene. 93934
OMIA:002072 The causative mutation is a G to A substitution in exon 6 of the Choline O-acetyltransferase gene (ChAT). This changes an amino acid codon from valine to methionine (Proschowsky et al., 2007). CFA28 9615
OMIA:000913 "Of the 85 SNPs detected by Feng et al. (2014) within the 18.9kb candidate region, only one showed perfect segregation with the silky-feather trait, namely ""a C to G transversion at 70,486,623 bp (ss666793747)"". Confirmation of this as a causal mutation was reported by the same authors: ""We genotyped ss666793747 in 718 birds from 33 populations and found that all 337 silky-feather chickens were homozygous G/G, 341 wild-type chickens were homozygous C/C and 40 known heterozygous birds were G/C (Table 2). These results lead to the hypothesis that ss666793747 is the causal mutation responsible for the silky-feather phenotype."" Noting that ""The candidate mutation ss666793747 is located between the SOBP and PDSS2 genes, which are two adjacent genes separated by 16.7 kb."" and that ""The ss666793747 mutation is 103 bp upstream of the initiator codon ATG of PDSS2 and 16.6 kb upstream of SOBP"", Feng et al. (2014) designated ""the ss666793747 mutation as PDSS2(-103C-G)"". Expression analyses enabled Feng et al. (2014) to conclude that ""The silky-feather mutation significantly decreases the expression of PDSS2 during feather development in vivo. Consistent with the regulatory effect, the C to G transversion is shown to remarkably reduce PDSS2 promoter activity in vitro""." "As summarised by Dorshorst et al. (2010) "" Initial linkage mapping studies suggested the Silkie gene (h) was 43 map units from the naked neck gene (Na) in linkage group III, now known as chromosome 1 (Warren 1938; Hutt 1949). However, it was subsequently shown that Na was located on chromosome 3 suggesting that h was also on this autosome (Pitel et al. 2000)."" Dorshorst et al. (2010) confirmed the chromosome to be GGA3, and provided data supporting a location within a 15.7Mb region in which the highest association was with a marker at 69.7Mb.
Feng et al. (2014) independently confirmed the above map location via genome-wide linkage analyses in the China Agricultural University Resource Population (CAURP) comprising 31 F0 (12 White Plymouth Rock and 19 Silky), 19 F1 and 229 F2 individuals, first in an analysis involving 125 microsatellites, and then in an analysis of SNP genotypes from the Illumina Chicken 60K SNP Beadchip, the latter pinpoiting the locus to ""a 380 kb interval between positions 70,201,106–70,581,126 bp [on chromosome GGA3; RJF genome sequence galGal3, assembled by the Washington University Genome Sequencing Center (WUGSC]"". Subsequent identity-by-descent mapping in the same population narrowed the locus to a ""56.7-kb interval (70,447,648–70,504,365)"". Haplotype analysis and resequencing narrowed it further to 18.9kb (70,468,129–70,487,067 bp)." 9031
OMIA:000419 "Adopting the comparative candidate-gene approach (based on similarity of diagnostic signs with humans), Seppälä et al. (2013) sequenced the canine GAA gene (encoding acid α-glucosidase) in ""two affected Finnish Lapphunds, their dam and an unrelated healthy 8-year-old Finnish Lapphund as control"", revealing a causal nonsense mutation: a ""c.2237G>A mutation leading to a premature stop codon at amino acid position 746"", i.e. p.W746*. Using a cell line established decades ago from tongue tissue, the authors ""were able to establish that one of the originally described Swedish Lapphunds with Pompe disease (born in 1979) was also homozygous for the same c.2237G>A mutation"". Exactly the same mutation in the human GAA gene causes the same disease (see the MIM entry above)." 9615
OMIA:001622 "Starting with a bacterial artificial chromosome (BAC) containing ""a portion of chicken chromosome 28 [GGA28] that conferred susceptibility to ASLV(C) infection"", Elleder et al. (2005) identified the TVC gene and showed that it most closely resembles mammalian butyrophilin encoded by BTN1A1. They also showed that resistance is due to a nonsense mutation (TGC[cysteine]55TGA[term]) that ""would produce a severely truncated Tvc receptor""." Payne and Pani (1971) presented evidence that the locus for this entry, TVC, is linked to the locus for resistance to type A viruses (see OMIA 001299-9031). The linkage evidence was strengthened by Pani (1974). Elleder et al. (2004) linkage-mapped the TVC locus to chicken chromosome GGA28, and showed that it is very close to the TVA locus. 9031
OMIA:002110 By whole-genome sequencing a single SDCA2 affected Belgian Shepherd, and comparing the data with genome sequences from 146 control canids, Mauri et al. (2017) identified a 227 bp SINE insertion into exon 2 of the ATP1B2 gene in the affected dog. The variant was described as XM_546597.5:ATP1B2:c.130_131insLT796559.1:g.50_276 or CanFam3.1:Chr5:32,551,064_32,551,065insLT796559.1:g.50_276. The SINE insertion was homozygous in 5 affected dogs. It did not occur in homozygous state in 258 control Belgian Shepherds. The variant was absent from 503 dogs of diverse other breeds. At the time of the canine study, there were no reports about human patients with ATP1B2 variants available. However, an Atp1b2 knockout mouse model displayed also a progressive motor impairment and spongy degeneration of the brain. Mauri et al. (2017) investigated the molecular consequences of the SINE insertion. Using skin RNA from one case, the authors detected at least three different aberrant splice isoforms. The epxressed transcripts all maintained the original reading frame. However, as several codons were altered in each of these isoforms, a loss of ATP1B2 function seems likely. Mauri et al. (2017) investigated a single family of Belgian Shepherd dogs (Malinois variety) consisting of both parents and a complete litter with 11 offspring to map the causative locus. Four out of the 11 puppies were affected by SDCA2. Using a combined linkage and homozygosity mapping approach the authors mapped the disease causing variant to Chr5:29,906,132–40,470,236 (CanFam 3.1 assembly). 9615
OMIA:001824 "Using inferred haplotypes from the 1000-bull-genomes project, Hayes et al. (2013) announced the discovery of the likely HH3 causal mutation.
Using exome capture and next-gen sequencing, McClure et al. (2014) confirmed and validated Hayes et al. (2013)'s causal mutation mutation as ""a non-synonymous SNP (T/C) within exon 24 of the Structural Maintenance of Chromosomes 2 (SMC2) on Chromosome 8 at position 95,410,507 (UMD3.1). This polymorphism changes amino acid 1135 from phenylalanine to serine and causes a non-neutral, non-tolerated, and evolutionarily unlikely substitution within the NTPase domain of the encoded protein. . . . Given the essential role of SMC2 in DNA repair, chromosome condensation and segregation during cell division, our findings strongly support the non-synonymous SNP (T/C) in SMC2 as the likely causative mutation.""
Full details of the Hayes et al. (2013) discovery were provided by Daetwyler et al. (2014). In summary: ""There was a single bull identified as a carrier of the derived HH3 region in the 1000 bull genomes project data set on the basis of the inferred haplotype. After filtering for mutations that were (i) carried in the heterozygous state by the HH3 carrier bull, (ii) absent in the 63 predicted non-carrier Holstein bulls, (iii) absent in the homozygous state in the Holstein bulls with unknown status and (iv) absent in the other breeds (assuming that the deleterious mutation is recent), only 1 candidate mutation was retained in the HH3 region: a thymine-to-cytosine transition at position 95,410,507 (g.95410507T>C) [UMD3.1]."" For validation, the mutation ""was genotyped by PCR and Sanger sequencing in a panel of 10 known HH3 carriers; all were heterozygous for the mutation, supporting the association between the HH3 region and the g.95410507C allele. As an additional test, 5,606 Holstein individuals were each genotyped in duplicate for the g.95410507T>C mutation using a custom Illumina BeadChip (all duplicate pairs were concordant). In agreement with the hypothesis that this mutation causes embryonic lethality, no individual with a CC genotype was detected (P < 0.06), whereas 2,476 individuals with the TT genotype and 171 individuals with the TC genotype were identified. In addition, 2,344 Montbeliarde individuals and 615 Normandy individuals were homozygous for the wild-type allele.""" " Using genotype data from tens of thousands of North American Holsteins, Jerseys and Brown Swiss cattle each genotyped with approximately 50K SNPs on the BovineSNP50 BeadChip, VanRaden et al. (2011) identified five new recessive lethal haplotypes by searching for common haplotypes that are never homozygous in live animals. Three of these haplotypes occur in Holsteins only, and (following a convention proposed by breed-association staff) VanRaden et al. (2011) named them HH1, HH2 and HH3, where the first H stands for Holstein and the second H for haplotype. The disorder described in this OMIA entry is HH3, which maps to chromosome BTA8, at 90-95Mb (UMD 3.0 genome assembly). Fritz et al. (2013) confirmed the existence and location of this deleterious haplotype.
By genotyping each of 7,937 Nordic Holstein bulls with the BovineSNP50 BeadChip, yielding 36,387 informative autosomal SNPs, and then searching for 25-marker haplotypes that never occur as a homozygote where the minimum expectation is 6 occurrences, Sahana et al. (2013) ""identified 17 homozygote deficient haplotypes which could be loosely clustered into eight genomic regions harboring possible recessive lethal alleles"". One of the eight regions (marked by haplotypes 08-1276, 08-1301, 08-1326 and 08-1351) seems to coincide with HH3.
McClure et al. (2014) refined the map location of haplotype HH3 on chromosome BTA8 to 95,057,877 to 95,468,310 (UMD3.1)." 9913
OMIA:001505 "By cloning and sequencing a very likely candidate gene (based on ""a striking deficiency of [lysosomal enzyme] cathepsin D activity in the CONCL brain and liver compared with controls""), Tyynelä et al. (2001) reported the causal mutation in Swedish Landrace as being ""A single nucleotide mutation [G->A] in the cathepsin D gene results in conversion of an active site aspartate to asparagine, leading to production of an enzymatically inactive but stable protein.""" 9940
OMIA:001271 "Noting that the relevant region of chromosome ECA1 contains the ACAN gene that has been implicated in similar types of dwarfism in cattle (see OMIA 001271-9913) and humans (see MIM entry above), Eberth (2013) sequenced this comparative positional candidate gene in affected and normal horses, revealing four variants strongly associated with dwarfism: c.245del, p.K82fx in exon 2 (Acan-D1); c.1270G>A, p.V424M in exon 6 (Acan-D2); c.6700delC, p.P1875fx in exon 11 (Acan-D3); c.7299-7319del, p.F2433-O2440del in exon 15 (Acan-D4). To FN's best knowledge, none of these has been published in the peer-reviewed literature.
Bailey (2014) mentions Eberth's discovery, but makes no mention of any specific likely causal variant.
Metzger et al. (2017) reported a missense mutation (g.94370258G>C; p.A505P) as a likely causal variant in Miniature Shetlands." By conducting a GWAS on 20 dwarf and 26 control Miniature horses, each of which had been genotyped with the Illumina Equine SNP50 chip (yielding 40,368 informative SNPs), Eberth (2013) mapped this disorder to a region on chromosome ECA1. 9796
OMIA:001356 "Rosengren Pielberg et al. (2008) presented convincing evidence that this classic phenotype is due to a 4.6kb intronic duplication in the gene for syntaxin-17 (STX17). This duplication appears to increase the expression of both syntaxin-17 and a neighbouring gene NR4A3, which encodes nuclear receptor subfamily 4, group A, member 3. Whilst the details are still to be elucidated, Pielberg et al. (2008) present circumstantial evidence that overexpression of one or both of these two genes leads to a hyperproliferation of hair-follicle melanocytes, leading to a gradual depletion of progenitor stem cells, and hence to a gradual loss of hair pigmentation as the animal ages. At the same time, the overexpression of one or both of these genes leads to a proliferation of dermal melanocytes in glabrous skin (skin that naturally lacks hair), which predisposes to melanoma development.
Curik et al. (2013) provided evidence that ""the STX17 mutation explains to a large extent the moderate to high genetic correlations among [melanoma grade, grey level, vitiligo grade, and speckling grade] . . . , providing an example of strong pleiotropic effects caused by a single gene"". Leeb (2013) provides a very informative summary of the results of Curik et al. (2013)." Rosengren Pielberg et al. (2005) fine-mapped this locus to a region less than 3 cM between two genes (NANS and ABCA1) on ECA25. Comparative mapping with humans and mice suggested no obvious candidate genes in this region, implying that this coat colour is due to a mutation in a gene not yet identified. 9796
OMIA:001158 "Noting that the only functional comparative gene in the candidate region of HSA19 was GYS1, McCue et al. (2008) sequenced this gene in a likely homozygous affected horse and a control horse, discovering a missense mutation (c.?G>A; p.Arg309His) whose segregation in other affected and normal horses was consistent with causality. Interestingly, McCue et al. (2008) presented evidence that this is a gain-of-function mutation: ""it is more likely that the glycogen accumulation in PSSM horse muscle is due to the Arg309His mutation and results from enhanced activity and/or poor regulation of the mutant enzyme""." By conducting a genome scan on 48 related affected and 48 unrelated normal Quarter Horses, each genotyped with 105 microsatellites spread across all chromosomes, McCue et al. (2008) mapped this disorder to the vicinity of microsatellite NVEQ018 on chromosome ECA10p. Genotyping the same and additional horses with additional ECA10p microsatellites narrowed the location corresponding to a 3 Mb region of human chromosome HSA19 from 51.9 Mb to 54.6 Mb. 9796
OMIA:000220 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Ding et al. (2002) identied a causal mutation in the canine DNA-PKcs gene as ""a point mutation [which] results in a stop codon at nucleotide 10,828 and premature termination at a position 517 amino acids before the normal C terminus resulting in a functionally null allele"". The gene is now called PRKDC in dogs and DNAPK in horses (in which the same disorder is due to mutations in the homologous gene)." 9615
OMIA:001462 "Rahman et al. (2012) reported the causal mutation in Toy Poodles as being a ""single base pair deletion of guanine in exon 3 [of the canine HEXB gene] was identified at nucleotide position 283 of the putative open reading frame (c.283delG). This mutation has the potential to cause a frameshift resulting in the alteration of valine at amino acid position 59 to a stop codon (p.V59fsX)."" This is the first published report of a causal mutation for this disorder in dogs." 9615
OMIA:000991 "Révay et al. (2012) reported that this disorder in a family of American Quarter Horses is due to ""a transition in the first nucleotide of the [androgen receptor] AR start codon (c.1A>G)"", with the result that ""a reduced amount of the functional AR is expressed during androgen-critical periods of development in the XY genetic male embryo, which alters its gonadal development and results in the observed phenotype"". This is the first report of a mutation in the AR gene in domestic animals.
In a ""Warmblood horse pedigree segregating AIS"", Welsford et al. (2017) ""provided evidences that a 25-bp deletion of the DNA-binding domain [of the AR gene] is causative"" in this breed." 9796
OMIA:001985 In a preprint posted on the Cold Spring Harbor bioRxiv preprint server on 15th January 2016, Schwarzenbacher et al. (2016) documented the likely causal mutation as a 1bp frameshift deletion on chromosome BTA3: rs723240647, g.15079217delC, ENSBTAT00000027126:c.4285_4287delCCCinsCC, p.Glu1430LysfsX66 in exon 20 of the GON4L gene. A peer-reviewed version of this paper (by the same authors; see list below) was published on 31 March. "In a preprint posted on the Cold Spring Harbor bioRxiv preprint server on 15th January 2016, Schwarzenbacher et al. (2016) reported mapping this autosomal recessive disorder to a ""1.85 Mb segment (14.88 Mb – 16.73 Mb)"" segment of chromosome BTA3. A peer-reviewed version of this paper (by the same authors; see list below) was published on 31 March." 9913
OMIA:001897 Frameshift insertion: c.504_505insC; chr8:80111598; UCSC assembly equCab2 (Finno et al., 2015) By conducting a GWAS on 15 affected and 17 non-affected Connemara ponies, each genotyped with the Illumina SNP70 Genotyping Beadchip (yielding 51,453 informative SNPs), Finno et al. (2015) mapped this disorder to a 1.7Mb region on horse chromosome ECA8: 79,936,024–81,676,900 bp; UCSC assembly equCab2 9796
OMIA:001913 "Sanger sequencing of the six candidate variants (see Mapping section above) in additional cases and controls revealed the most likely causal mutation to be an ""RAB24 SNP polymorphism [which] was an A to C transversion located at position 113 [c.113A>C] in the first of its eight exons . . . [which] produced an amino acid change from glutamine (Q) to proline (P) at position 38"" (p.Q38P). Sequencing of the RAB24 exons in affected dogs from other breeds revealed the same allele to be potentially causative in Gordon Setters. Subsequent sequencing and SNP genotyping within this breed provided strong supportive evidence for the c.113A>C, p.Q38P mutation being causal in this breed." "From a genome scan of ""Forty-eight related Old English Sheepdogs, including eight affected dogs"", each genotyped with 311 microsatellites (yielding 264 informative markers), Agler et al. (2014) mapped this disorder to a 17MB region on chromosome CFA4. Fine-mapping with additional markers confirmed but did not narrow this region. The same authors then conducted a GWAS on the same 48 dogs plus 6 additional affected animals from the same breed, each genotyped with the ""Illumina Infinium CanineSNP20 Beadchip (22 dogs)"" or ""CanineHDBeadchip (32 dogs)"" (yielding 12,986 informative SNPs), narrowing the candidate region on CFA4 to between 36Mb and 42Mb. Sequencing of this candidate region on CFA4 via targeted sequence capture in three affected and three non-affected dogs, followed by filtering of the identified variants, narrowed down the field to six missense mutations in five genes. " 9615
OMIA:001437 "Braunschweig and Leeb (2006) showed that a ""C to A transversion at position 215 bp upstream of the translation initiation site"" of the bete-lactoglobulin (LBG) gene segregates with aberrant low expression of beta-lactoglobulin. Other symbols for this gene are BLG and PAEP, the latter being the official NCBI symbol." This trait maps to the actual LBG gene (11q28) 9913
OMIA:000540 Chen et al. (2013) reported evidence that the HR gene in cetaceans, including Balaenoptera omurai, has degenerated into a non-functional pseudogene, which is consistent with the hairlessness of this species. 255217
OMIA:001079 9913
OMIA:002020 Ainsworth et al. (2015): an A>T SNP in an intron donor site (c.1256+2T>A) 9615
OMIA:000373 "Adopting a comparative positional cloning approach (by noting that the chromosomal region to which this trait maps in chickens is orthologous with the region of mouse chromosome MMU 10 that includes the PMEL17 gene which when mutated causes the silver mutation in mice), Kerje et al. (2004) were able to identfy the causal mutation: ""The Dominant white allele [is] exclusively associated with a 9-bp insertion in exon 10 [of the PMEL17 gene], leading to an insertion of three amino acids in the PMEL17 transmembrane region. Similarly, a deletion of five amino acids in the transmembrane region occurs in the protein encoded by Dun. The Smoky allele shared the 9-bp insertion in exon 10 with Dominant white, as expected from its origin, but also had a deletion of 12 nucleotides in exon 6, eliminating four amino acids from the mature protein."" (Kerje et al., 2004). In chickens, the gene encoding PMEL17 is called PMEL." 9031
OMIA:002022 "Agerholm et al. (2016): ""a single base deletion in the first exon of CHRNB1 (c.55delG) introducing a premature stop codon (p.Ala19Profs47*) in the second exon, truncating 96 % of the protein.""" "Agerholm et al. (2016): ""a single genomic region of extended homozygosity of 21.5 Mb on chromosome 19""" 9913
OMIA:001947 "Comparison of the whole-genome sequence of one of the affected Eurasier dogs with similar data from 47 dogs of other breeds enabled Gerber et al. (2015) to narrow the candidate field down to 4 non-synonymous variants. Genotyping of these four variants in 34 Eurasier dogs revealed only one variant that co-segregated perfectly with the disorder allele: a single bp deletion in VLDLR (c.1713delC) which ""results in a frameshift and premature stop codon. It is predicted to truncate more than a third of the encoded very low density lipoprotein receptor (p.W572Gfs*10)""." By conducting a GWAS involving 9 affected and 11 normal Eurasier dogs, each genotyped with the Illumina HD SNP chip (yielding 110,848 informative markers), Gerber et al. (2015) mapped this disorder to the 90.9–94.2 Mb region of canine chromosome CFA1 (CanFam 3 assembly). Subsequent homozygosity mapping confirmed this candidate region. 9615
OMIA:001357 "Bodin et al. (2007) reported a causal mutation as ""a C53Y missense nonconservative substitution [in BMP15] leading to the aminoacidic change of a cysteine with a tyrosine in the mature peptide of the protein. As for other mutations found in the same gene, this is associated with an increased ovulation rate and sterility in heterozygous and homozygous animals, respectively. Further in vitro studies showed that the C53Y mutation was responsible for the impairment of the maturation process of the BMP15 protein, resulting in a defective secretion of both the precursor and mature peptide""." 9940
OMIA:001432 "In miniature longhaired dachshunds with this disorder, Mellersh et al. (2006) discovered a 44-bp insertion in exon 2 of the RPGRIP1 gene that encodes retinitis pigmentosa GTPase regulator-interacting protein 1. The insertion results in a frameshift, which in turn creates a premature stop codon. At the time, this appeared to be the causative mutation, and was so listed in OMIA. However, subsequent studies (Miyadera et al., 2009; Busse et al., 2011; Miyadera et al., 2012; Mammalian Genome 23: 212-223) raised some doubts about this conclusion. These doubts were confirmed by Kuznetsova et al. (2012). This disorder was, therefore, re-categorised in OMIA as being without a known causative mutation.
The PlosONE paper by Miyadera et al. (2012) has caused the above decision to be reversed! These authors commenced by noting that RGRIP1 is the key gene for the homologous human disorder and that there is no other possible candidate gene in canine mapped region. Tellingly, they provide substantial evidence for ""leakiness"" of the causal insertion in RGRIP1 attributable to ""transcriptional or translational frameshifting in RPGRIP1 expression"" which occurs at levels ""unprecedented in eukaryotic cellular genes"". They conclude that ""The frameshifting observed here can contribute to leakiness of the RPGRIP1−/− mutation in vivo in cord1 dogs, accounting for the survival of vision in some affected animals until late in life"". These authors also suspect that the extent of ""leakiness"" is affected by alleles at a modifier locus first reported by Miyadera et al. (2012; Mammalian Genome 23: 212-223). On the strength of these conclusions, RGRIP1 has been reinstated as the key gene for this disorder!" By conducting a GWAS on 31 affected and 49 control Miniature longhaired dachshunds, each genotyped with the Canine SNP20 SNP chip, Miyadera et al. (2012) highlighted a region on chromosome CFA15. 9615
OMIA:000715 The causative variant is a 3 bp deletion in exon 14 of MFN2, the gene that codes for mitofusin 2. This c.1617_1619delGGA deletion is predicted to lead to the loss of a glutamate residue on the protein level, p.Q539del. (Fyfe et al., 2011). Fyfe et al. (2011) mapped this disorder by linkage mapping with microsatellites to the telomeric end of chromosome CFA2. 9615
OMIA:001139 Tan et al. (1997) documented the first cases of ovine McArdle's disease, and then, by cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), showed the cause to be a G>A substitution at the 3' splice site of intron 19 of the gene for glycogen myophosphorylase, giving rise to an 8-base deletion at the 5' end of exon 20, creating a frameshift, and resulting in a premature stop codon which removes the last 31 amino-acids from the protein. The mutation is being maintained in a flock of carrier sheep. 9940
OMIA:001057 "As reported by Boudreaux (2012), a causal mutation for this disorder in Doberman Pinchers was reported in US Patent 6074832, submitted by Brewer et al. (Michigan State University) in 2000. According to the patent, the actual mutation is a synonymous base substitution at nucleotide 7437 in exon 43 (Ser 2479) of the VWF gene, which decreases the effectiveness of a splice site. Gentilini and Turba (2013) provided details of the mutation: it is ""a G → A transversion of the last nucleotide of von Willebrand factor (vWf) exon 43 (c.7437G > A, NM_001002932.1) . . . [which] activates a cryptic splice site a few nucleotides upstream of the normal splice site, leading to a frame shift that results in the formation of a truncated protein of 119 amino acids""." 9615
OMIA:001208 "Van Poucke et al. (2016): ""c.719G>A nucleotide substitution resulting in a p.Arg240His substitution was considered to be causal, because it is orthologous to the heterozygous de novo dominant c.716G>A (p.Arg239His) hotspot variant in man, proven to cause a severe phenotype. In addition, the variant was not found in 50 unrelated healthy Labrador retrievers.""" 9615
OMIA:000698 "By cloning and sequencing the most likely comparative candidate gene (namely CLCN1, based on similarity of clinical signs across species), Borges et al. (2013) showed that this disorder in Murrah buffalo is due to a SNP in exon 3 (c.396C>T) which creates a ""splice donor site located at nucleotides 90–91 of exon-3. The predicted impact of this aberrant splicing event is the alteration of the CLCN1 translational reading frame, which results in the incorporation of 24 unrelated amino acids followed by a premature stop codon.""" 89462
OMIA:001951 Kromik et al. (2015; Genetics): c.196A>G; p.66Lys>Glu; NM_001192985.1 9913
OMIA:000151 "Using mate-pair libraries from one affected and three controls, Charlier et al. (2012) obtained around 3.4Gb of sequence from each animal. Comparison of sequence in the candidate BTA21 region ""revealed a 3.3 Kb deletion removing exons 25–27 of the 37 composing the FANCI (Fanconi anemia complementation-group I) gene"". Noting that the carrier frequency is far too high (up to 7.4%) to be consistent with a relatively rare autosomal recessive disorder, Charlier et al. (2012) also showed that a large proportion of affected calves die in utero. Thus this causal mutation also contributes to natural abortions and hence to reduced fertility." "In the course of their large-scale study of BovineSNP50 BeadChip haplotypes that are common but never homozygous, VanRaden et al. (2011) mapped this disorder to BTA21 at 20-25Mb (UMD 3.0 genome assembly).
Genotyping six affected Holstein-Friesian calves and 15 normal H-F controls with a custom-made 50K bovine SNP chip, followed by autozygosity mapping, enabled Charlier et al. (2012) to map this disorder to a 2.46Mb region of chromosome BTA21, which contains 56 annotated genes.
Fritz et al. (2013) confirmed the existence and location of this deleterious haplotype.
By genotyping each of 7,937 Nordic Holstein bulls with the BovineSNP50 BeadChip, yielding 36,387 informative autosomal SNPs, and then searching for 25-marker haplotypes that never occur as a homozygote where the minimum expectation is 6 occurrences, Sahana et al. (2013) ""identified 17 homozygote deficient haplotypes which could be loosely clustered into eight genomic regions harboring possible recessive lethal alleles"". One of the eight regions (marked by haplotypes 21-276, 21-301 and 21-326) seems to coincide with Brachyspina." 9913
OMIA:001443 The causative variant is a c.829T>C transition in exon 7 of CLN6 leading to p.W277R on the protein level (Katz et al., 2011). Affected dogs have CLN6 deficiency. The function of CLN6 is unknown, but is likely an intrinsic membrane protein with 7 transmembrane domains (Katz et al., 2011). CFA30 9615
OMIA:001346 "Kijas et al. (2002) discovered an autosomal-dominant progressive retinal atrophy in English Mastiff dogs, with clinical signs very similar to a human dominant retinitis pigmentosa that is due to mutations in the gene for rhodopsin. Taking the rhodopsin gene as a strong comparative candidate, Kijas et al. (2002) sequenced all five exons of the canine rhodopsin gene from a heterozygous affected dog, and discovered a missense mutation (C-to-G transversion) at nucleotide 11, giving rise to a Thr-to-Arg amino acid substitution at position 4 of the peptide (T4R), in the extracellular domain. Noting that the mutation generates a BsmFI restriction fragment length polymorphism, Kijas et al. genotyped 26 affected and 21 related normal English Mastiffs. Three of the affected dogs were homozygous for the mutant allele; the rest were heterozygous. All related normal dogs were homozygous for the normal allele, as were 156 normal dogs from 17 other dog breeds [Frank Nicholas, 26 June 2002]
Kijas et al. (2003) noted that ""Testing of PRA-affected animals from [other] 16 breeds revealed that none carry the T4R mutation, indicating a different cause of PRA""." 9615
OMIA:001245 "By cloning and sequencing a very likely candidate gene on the basis of the physiology and biochemistry of the disorder in chickens, and on the homologous disorder in humans, Semple-Rowland et al. (1998) cloned and sequenced the chicken photoreceptor guanylate cyclase gene, and identified the causative mutation as an indel in that gene, resulting in a peptide that ""is predicted to lack the membrane-spanning domain and the regions immediately flanking it, a region essential for proper folding and enzyme activity"".
Semple-Rowland and Cheng (1999) showed that ""both the rd and rc chickens carry the same GC1 null mutation"", and proposed replacing the symbols ""rd"" and rc"" with GUCY1*." 9031
OMIA:002035 Charlier et al. (2016): frame-shift p.Lys127Valfs∗28 9913
OMIA:000785 The molecular basis of this disorder was first reported by Rudolph et al. (1992, Nature Genetics). Having established that the horse gene for adult skeletal muscle sodium channel is completely linked with this disorder (see Mapping section above), Rudolph et al. (1992, Nature Genetics) identified the causative mutation as a missense mutation in the gene encoding the alpha chain of the adult skeletal muscle sodium channel, resulting in increased sodium permeability across the skeletal muscle cell membrane. Noting that this disorder in horses is very similar to a disorder in humans which is due to mutations in the adult skeletal muscle sodium channel gene, Rudolph et al. (1992, Animal Genetics) isolated the orthologous horse gene, which they then showed is completely linked (theta = 0) to the horse disorder. This disorder therefore provides an excellent example of how knowledge of comparative genetics can be put to good use in elucidating the molecular basis of disorders. 9796
OMIA:001551 "Lyons et al (2016): ""A long-term project that initiated with targeted linkage analysis, and, as domestic cat genomic resources improved, progressed to identity by descent mapping, homozygosity mapping and a genome-wide case-control association study (GWAS) suggests ALX1 as a major gene controlling craniofacial structure and the variant in ALX1 is associated with the Burmese brachycephaly and the craniofacial abnormality"". ""Sequence analysis identified a 12 bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese."" " "Lyons et al. (2016) reported that ""Family-based linkage analysis localized the trait to cat chromosome B4""." 9685
OMIA:002112 "Campbell et al. (2001): ""a mutation in which nucleotides 3991-3994 (""CTAG"") were replaced with ""TGTCATTGG."" The first seven bases of the inserted sequence were identical to nucleotides 4002-4008 of the normal canine COL1A2 sequence. The resulting frameshift changed 30 amino acids and introduced a premature stop codon.""" 9615
OMIA:002068 "By comparing genomic sequence in the candidate region from 4 dwarf Friesians, 3 non-affected Friesian controls, the horse reference genome and a Quarter Horse (a breed in which dwarfism has not been reported), Leegwater et al. (2016) identified a likely causal (missense) variant in Friesians as g.4535550C>T; c.50G>A; p.Arg17Lys in B4GALT7. The point mutation concerns the last nucleotide of exon 1 and Leegwater et al. (2016) demonstrate that it leads to a splicing deficiency of B4GALT7 transcripts. Consistent with the variant being causal, Leegwater et al. (2016) reported that ""All 29 dwarfs of which DNA was available were homozygous for the mutation . . . . The 8 obligate carriers were heterozygous . . . and of a group of 177 Friesian horses 22 were carrier of the mutation and 155 were homozygous for the reference allele"". " "By conducting a GWAS on 10 affected and 10 normal Friesian horses, each genotyped with the equine SNP50 chip (yielding 34,429 informative SNPs), Orr et al. (2010) mapped this disorder to a 2Mb region of chromosome ECA14.
Via an independent GWAS involving 19 Friesian dwarfs and 65 non-affected Friesian controls, each genotyped with the Illumina® EquineSNP50 Genotyping BeadChip (yielding 29,840 informative SNPs), Leegwater et al. (2016) confirmed this location, specifying the region as ""between positions 3151847 and 6229282 on ECA14""." 9796
OMIA:001879 "Using the direct candidate gene strategy, based on clinical signs, Brons et al. (2013) identified ""in-frame 6 bp deletion removing 2 of the 3 adjacent threonine residues in exon 6 of the SLC3A1 gene"" (c.1095_1100del; p.Thr366_Thr367del) as causal in Australian Cattle Dogs." 9615
OMIA:001435 "Nadeau et al. (2006) showed that this feather colour is due to missense mutation in the MC1R gene: ""a G-to-A substitution leading to a Glu92Lys mutation . . . is likely to be the causative mutation for the increased melanism in [the] Extended brown"" feather-colour phenotype." 93934
OMIA:001887 "Comparison of whole-genome sequence by Sartelet et al. (2014), from four affecteds and eight control Belgian Blue non-carriers, revealed three SNVs ""[c2244G>C + c2248T>C + c2250C>A] located in exon 23 of the CLCN7 gene encoding the anion transport protein ClC-7"". The first of these is synonymous, but the second and third jointly cause ""a tyrosine to glutamine substitution (TAC>CAA: Y750Q)"" in a highly conserved region of the protein. Subsequent genotyping for the two Y750Q missense mutations in ""63 cases, 74 of their parents, 141 animals from 11 breeds other than BBCB, and 6,489 healthy BBCB animals"" confirmed the causality of these mutations: ""All cases were homozygous for the Y750Q mutation, while available parents and putative founder (Gabin) were all carriers. The mutation was absent in the non-BBCB cohort, and detected at a frequency of 5% (644 carriers) in BBCB controls. None of the genotyped controls was homozygous for the mutant (p=0.000026 under Hardy Weinberg equilibrium).""" "By conducting a GWAS on 33 affected and 275 controls (each genotyped with a custom 50K SNP chip; Charlier et al., 2008, Nat Genet 40, 449-454), Sartelet et al. (2014) mapped this disorder to the proximal end of chromosome BTA25. Subsequent ""Visual examination of the SNP genotypes defined a non-recombinant autozygous interval of 1.15 Mb (Bovine Genome assembly bTau6 (UMD3.1), chr25: 632,647-1,781,139) shared by all 33 cases and encompassing 82 annotated transcripts"". " 9913
OMIA:000385 "Nicol et al. (2009) identified the causal mutation of Thoka fecundity as ""a single base change (A1279C) resulting in a nonconservative amino acid change (S109R) in the C-terminus of the mature GDF9 protein, which is normally expressed in oocytes at all stages of development""." 9940
OMIA:000483 "The gene nearest to the SNPs with the strongest association in the candidate region on OVA10 is the gene for Relaxin-like receptor 2 (RXFP2). Johnston et al. (2011) provided strong evidence for this gene's primary involvement in horn development. Specifically, they designated the two alleles of a C>T SNP in the 3' UTR of RXFP2 as alleles Ho+ (wild type) and HoP (polled or scurred), respectively.
Gene expression studies of RXFP2 by Allais-Bonnet et al. (2013) showed differential expression in horn-bud tissues from polled and horned cattle, thereby establishing a link between polledness in sheep and cattle.
By sequencing the candidate RXFP2 region in seven Swiss sheep breeds, Wiedemar and Drögemüller (2015) discovered a ""1833-bp genomic insertion located in the 3'-UTR region of RXFP2 present in polled animals only"". Interestingly, they provided ""evidence that the polled-associated insertion adds a potential antisense RNA sequence of EEF1A1 to the 3'-end of RXFP2 transcripts"".
He et al. (2016) reported that ""a PCR analysis for the detection of the 1.8-kb insertion associated with polled sheep in other breeds failed to verify the association with polledness in the three Chinese breeds""
Following a large-scale investigation, Lühken et al. (2016) reported that ""Multiplex PCR genotyping of 489 sheep from 34 breeds and some crosses between sheep breeds showed a nearly perfect segregation of the insertion polymorphism with horn status in sheep breeds of Central and Western European origin. In these breeds and their crossings, heterozygous males were horned and heterozygous females were polled."" However, ""in breeds with sex-dependent and/or variable horn status, especially in sheep that originated from even more southern European regions and from Africa . . . we observed almost all possible combinations of genotype, sex and horn status phenotype"". Thus, the insertion appears to be causal except in breeds ""with sex-dependent and/or variable horn status""." "Vaiman et al. (1996) discovered that the horns locus in goats is located in the distal region of goat chromosome 1. Since this chromosome of goats is homologous to one of the arms of sheep chromosome 1, it seemed possible that the horns gene in sheep is located on sheep chromosome 1. Interestingly, the horns gene in cattle is located on cattle chromosome 1, which is homologous to goat chromosome 1. However, the locations of the bovine and caprine horns genes are not homologous (Vaiman et al., 1996). The debate was settled by Montgomery et al. (1996; next paragraph) who showed that the horns locus in sheep is actually located on chromosome 10. Thus the horns loci of sheep, cattle and goats all appear to be different.
Montgomery et al. (1996) mapped this locus to the proximal end of OAR10 in a Romney-Merino cross flock, showing no recombinants with microsatellite AGLA226, whose location is OAR10q13. Beraldi et al. (2006) confirmed this location, in Soay sheep. Johnston et al. (2010) narrowed the region to 7.4cM in Soay sheep. Pickering et al. (2009) narrowed the region in domestic (New Zealand Romney x Merino backcross) sheep to 200kb. The OAR10 location of horns/polled in sheep bears no homology to the BTA1 location of horns/polled in cattle, suggesting that the same trait in the two species is determined by different genes.
In a genome-wide association study (GWAS) on 486 Soay sheep, each genotyped with the Ovine SNP50 BeadChip (yielding 35,831 informative SNPs) and phenotyped into normal, scurred and polled, Johnston et al. (2011) narrowed down the location of the horns/polled locus in Soay sheep to a 250kb region at around 29.4Mb on chromosome OVA10. A GWAS analysis on EBV for horn length on 160 of the above sheep confirmed this location.
In Australian Merino sheep, Dominik et al. (2012) genotyped each of 10 phenotyped rams and 918 of their phenotyped offspring with the Illumina ovine 50k SNP chip, yielding 48,640 informative SNPs. A linkage-disequilibrium analysis mapped the trait to ""a SNP located at Mb position 29.38 on sheep chromosome [OVA]10"", the nearest gene being RXFP2.
Also in 2012, when Kijas et al. genotyped each of 2,819 sheep from 74 different breeds with the Illumina Ovine 50K SNP chip and searched for signatures of selection by calculating FST for each of the 49,034 informative SNPs, they discovered that ""the strongest selection signal was identified immediately adjacent to RXFP2 [at Mb position 29.54 on chromosome OVA10] . . . Strong evidence supports that RXFP2 was targeted by breeding for the removal of horns, likely to be one of the oldest morphological modifications that accompanied domestication""." 9940
OMIA:000819 9615
OMIA:000865 "By cloning and sequencing a very likely candidate gene (based on detailed prior physiological and biochemical studies), Bujo et al. (1995; PNAS 92: 9905–9909) showed that this chicken disorder is due to a mutation in the gene encoding very low density lipoprotein receptor (VLDLR): ""The mutation converts a cysteine residue into a serine, resulting in an unpaired cysteine and greatly reduced expression of the mutant avian VLDLR on the oocyte surface.""" 9031
OMIA:000201 Schneider et al. (2015): the likely causal mutation is C126Y 61386
OMIA:001353 Brooks et al. (2015) reported that the likely causal variant for this disorder in German shepherd dogs is a splice-site mutation g.8912219 G>A in the TMEM16F gene (also known as ANO6). Using linkage analysis of data collected from a genome scan with 280 microsatellites genotyped on 28 affected and 27 control German shepherd dogs, Brooks et al. (2010) mapped this disorder to near the centromere of chromosme CFA27. 9615
OMIA:000703 "Armed with the mapping knowledge summarised in the Genetic mapping section above, Lin et al. (1999) performed a Herculean series of linkage and comparative physical mapping studies within a 1.8Mb region of chromosome CFA12, finally narrowed the chase down to one comparative positional candidate gene, namely HCRTR2, which ""encodes a G protein–coupled receptor with high affinity for the hypocretin neuropeptides"". They then reported that a ""SINE insertion mutation [in the HCRTR2 gene] is the cause of narcolepsy in Dobermans"". These same authors showed that the causative mutation in Labrador retrievers is a deletion of exon 6 due to a ""G to A transition in the 5′ splice junction consensus sequence (position +5, exon 6–intron 6)"". The work of Lin et al. (1999) was the subject of a commentary by Reilly (1999). The causative mutation in dachshunds is a G to A substitution at exon 1 of the HCRTR2 gene (Hungs et al., 2001). " By using RFLPs detectable via two comparative candidate genes, Mignon et al. (1991) were able to show that canine narcolepsy is not tightly linked to the canine MHC, but is tightly linked to the canine equivalent of the human switch region of the mu immunoglobulin heavy-chain gene (S_sub(mu)), which was later shown (by Lin et al., 1999) to be located on a section of chromosome CFA12 that is homologous to human chromosome HSA6. 9615
OMIA:001534 By cloning and sequencing a very likely comparative candidate gene (based on knowledge that the Mx gene product inhibits virus repliaction in other species), Ko et al. (2002) reported that a missense polymorphism at position 631 (Ser to Asn) of the chicken Mx gene confers susceptibility/resistance respectively, to viruses in chickens. The MX gene is now known as MX1. 9031
OMIA:001509 "Fine-mapping followed by sequencing of likely positional candidate genes resulted in Bader et al (2010) identifying the causal mutation as a missense mutation in ADAMTSL2: ""(c.660C>T) predicted a non-synonymous change, converting an arginine to a cysteine at codon 221 (R221C), occurred in a highly conserved stretch of residues, and was computationally predicted to negatively impact protein structure and function"". The publication of Bader et al. 2010 probably had an incorrect numbering of the cDNA in their variant designation. The correct variant designation should read XM_003639308.3:c.661C>T; p.Arg221Cys." By conducting a genome scan on 6 affecteds and 39 control Beagles, each genotyped for 719 microsatellites in a case-control design, Bader et al. (2010) mapped the disorder to a region on chromosome CFA9. 9615
OMIA:001578 Starting with some linkage mapping, and using the full power of current genomics tools, Fox-Clipsham et al. (2011) identified the causal mutation for this disorder as a missense mutation in the gene encoding solute carrier family 5 (sodium/myo-inositol cotransporter), member 3 (SLC5A3), on chromosome ECA26. This equine gene has the interim symbol of LOC100052070. 9796
OMIA:002038 Charlier et al. (2016): nonsense (stop-gain) p.Lys693∗ 9913
OMIA:000770 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous disorder in humans, mice and rats), Nadon et al. (1990) reported the causative mutation as ""a point mutation at position 219 of the coding sequence [of the PLP gene; now called PLP1] that results in a histidine to proline change in the protein"". According to the current variant nomenclature as of 2013 this corresponds to a c.110A>C or p.H37P missense variant." 9615
OMIA:000725 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Somers et al. (2003) showed that this disorder is due to a 2864G>C base substitution in the NPC1 gene, resulting in a C955S amino-acid substitution.
In an excellent example of Precision Medicine (and the first time this term has appeared in the 24,392 papers currently [29 Oct 2016] included in OMIA), Mauler et al. (2017) identified a novel likely causal (missense) variant (c.1322A>C; p.H441P) in the NPC1 gene by 25x whole-genome sequencing an affected cat and comparing its variants to those in the 99 Lives Cat Genome Sequencing database." 9685
OMIA:002071 "By sequencing the most likely comparative candidate gene (CHST6) in one affected and one normal Labrador Retriever, Tetas Pont et al. (2016) identified the likely causal mutation as c.814C>A; p.R272S. Supporting evidence was provided by evidence that ""six LR affected with MCD were homozygous for the mutant allele, while 140/151 control LR were homozygous for the wild-type allele and 11/151 were heterozygous for the mutation""." 9615
OMIA:001787 Karyadi et al. (2013) identified a copy number variant (CNV) of KITLG that is very strongly associated with SCCD in (dark-coloured) Standard Poodles. Interestingly, light-coloured Standard Poodles have the same CNV at the same frequency, but are not affected, which suggests an interaction between KITLG and a coat-colour gene (Karyadi et al., 2013). A GWAS with the Illumina CanineHD BeadChip on 24 dark-coloured and 24 light-coloured Standard Poodles implicated variation at the coat-colour gene MC1R as the only difference between the two types of Standard Poodles. A GWAS with the Affymetrix v2 Canine SNP Chip conducted by Karyadi et al. (2013) on 31 affected (dark-coloured) Standard Poodles and 34 unrelated black Standard Poodles, followed by fine-mapping, highlighted a 28.3kb region on chromosome CFA15, in which KITLG resides. 9615
OMIA:002061 "Cortimiglia et al. (2017): the likely causal variant involves two mutations, namely c.79C>T and c.79_80insT in exon 1, resulting in ""a frameshift
change and a premature stop codon at position 81 of the deduced protein sequence, which in the wild-type form contains 536 amino acids.""" 345164
OMIA:001248 "A molecular basis for this disorder was first reported by Giger et al. (2006): ""The coding sequence of feline GNPTA was 3657 bp long (1219 amino acids). There was close homology (.90%) between our feline and the published human GNPTA cDNA sequence. The cDNA sequences from affected and normal cats were practically identical except for a single nonsense point mutation C>T at bp 2655, which changes a glycine residue into a stop codon. This leads to premature termination of the coding sequence presumably resulting in a truncated non-functional protein in affected cats."" GNPTA is now called GNTPAB. [Thanks to Hamutal Mazrier for pointing this out to FN; 29 July 2013]" 9685
OMIA:001501 Brooks et al. (2010) identified a deletion in the MYO5A gene as being responsible for this disorder in Arabian horses. This gene has the interim symbol of LOC100069548. 9796
OMIA:001318 9615
OMIA:000668 "Guo et a. (2016) used ""genome-wide association (GWA) analysis, linkage analysis, Identity-by-Descent (IBD) mapping, array-CGH, genome re-sequencing and expression analysis to show that the Mb allele causing the Mb phenotype is a derived allele where a complex structural variation (SV) on GGA27 leads to an altered expression of the gene HOXB8. . . . The Mb allele differs from the wild-type mb allele by three duplications, one in tandem and two that are translocated to that of the tandem repeat around 1.70 Mb on GGA27""." Sun et al. (2015) mapped this trait to chromosome GGA27. 9031
OMIA:000664 By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), He et al. (1999) showed that the causative mutation is a 3 bp deletion in the IDUA gene, which results in removal of an aspartate residue from the finished polypeptide. 9685
OMIA:001743 "Marklund et al. (1998) showed that, like the dominant white allele, the patch allele is a duplication of KIT. The difference between the two alleles is that the dominant white allele also has a ""G to A substitution in the first nucleotide of intron 17 disrupting the highly conserved GT pair at the 5′ splice site"" resulting in the skipping of exon 17, whereas the patch allele does not have this substitution. From the results of genome sequencing of tens of pigs, Rubin et al. (2012) confirmed that the patch allele comprises a 450kb duplication that includes KIT (roughly in the middle)." Using RFLPs for two comparative (from mouse) candidate genes, namely ALB and PDGFRA, Johansson et al. (1992) reported that the dominant white/patch locus is very tightly linked to both ALB and PDGFRA (theta=0), which are on chromosome SSC8. A third comparative candidate gene, closely linked to ALB and PDGFRA in mice, could not be mapped in pig because no RFLP could be detected. However, given its close linkage to ALB and PDGFRA in mice and in humans, KIT was also a very strong comparative positional candidate gene for porcine dominant white/patch. 9825
OMIA:001366 Ali et al. (2011) identified a nonsense mutation in the MPDZ gene as the cause of this disorder. """Linkage analysis mapped the rdd locus to a small region of the chicken Z chromosome with homologies to human chromosomes 5q and 9p."" (Burt et al., 2003)" 9031
OMIA:001140 "Frameshift deletion: c.1360_1361delAA; p.Lys453Ilefs*3 (CanFam 3.1 boxer reference genome) ""resulting in premature truncation of 1461 amino acids from the 1916 amino acid protein"" (Wolf et al., 2015)" From a GWAS on 7 affecteds and 112 control Nova Scotia Duck Tolling retrievers, each genotyped with the Illumina CanineHD BeadChip (yielding 110,021 informative SNPs), Wolf et al. (2015) mapped this disorder to a 2.88Mb region on chromosome CFA27. Subsequent homozygosity mapping narrowed this to a 1.44Mb region, namely CFA27: 9.29–10.73 Mb 9615
OMIA:000309 By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Agarwal et al. (1994) discovered a deletion of 1773 bp in the 3' end of the coding region of the growth hormone receptor gene in the Connecticut (CT) strain of dwdw chickens. The region included in the deletion encodes 27 highly conserved amino acids and the stop codon. In the dw allele, the sequence of bases 3' of the deletion is such that the open reading frame extends to encode 27 new amino acids plus a further 26 amino acids, before reaching the transcription termination site. This mutant allele produces a novel peptide which is unable to fulfil the role of normal growth hormone receptor. 9031
OMIA:001503 "Abitbol et al. (2010) reported a likely causative mutation in American Staffordshire terriers as a c.296G>A transition in the gene encoding the lysosomal enzyme arylsulfatase G. The variant leads to the p.R99H substitution in the protein. Affected dogs are deficient in ARSG.
Nolte et al. (2016) reported the same variant in another affected American Staffordshire Terrier." CFA9 9615
OMIA:001949 c.1030_1033delCTGT deletion in FOXN1 (Abitbol et al., 2015) 9685
OMIA:001531 "Fine-mapping of the CFA13 candidate region (see Mapping section) narrowed the region to a 238kb segment containg only one gene, namely RSPO2, a likely functional candidate gene. Sequencing of this gene identified the causal mutation as a 167bp insertion ""within the 3′UTR at position 11,634,766"", which leads to a threefold increase in transcription of RSPO2 in muzzle skin of dogs with furnishings (Cadieu et al., 2009)." "By conducting a GWAS on ""33 wire-haired, 34 smooth coat, and 29 long-haired"" Dachsunds, each genotyped with an Affymetrix Version 2 Canine SNP chip (yielding 51,071 informative SNPs for analysis), Cadieu et al. (2009) highlighted a region on chromosome CFA13.
By conducting a mammoth proof-of-principle GWAS on ""4 breeds with furnishings (a coat type with moustache and eyebrows . . . ) compared to 42 without them"", with each dog being genotyped with Illumina CanineHD array (yielding 157,393 SNPs for analysis) developed for this study, Vaysse et al. (2011) confirmed the results of Cadieu et al. (2009) by highlighting a region between 10.42 and 11.68Mb on chromosome CFA13. Specifically, ""The most strongly associated SNP is at 11,678,731 (Pgenome<0.001), 44 kb from the causative SNP previously identified in RSPO2""." 9615
OMIA:000547 "In the words of Charlier et al. (2008): ""a missense mutation in exon 39 (A5804G) resulting in an H1935R substitution in the fourth extracellular loop"". The His (normal) form of the peptide is conserved in all vertebrates sequenced to date. (FN 080330)
" "In a pioneering use of tens of thousands of SNP markers (""using either the 25K Affymetrix SNP panel or a custom-made 60K Illumina panel""), Charlier et al. (2008) identified a single 11.78 Mb region on BTA2 in which 3 affected calves were significantly more homozygous for the same allele at each of many SNPs, when compared with 9 normal controls. An investigation of comparative candidate genes in this region identified the ABCA12 gene as a likely culprit. This gene encodes the 12th member of the A subfamily of ATP-binding cassette transporters. Some sequencing of this gene quickly identified the molecular lesion." 9913
OMIA:001339 By cloning and sequencing a very likely comparative candidate gene (based on the homologous disorder in other species), Kramer et al. (2004) showed that this disorder in German Shorthaired Pointers and German Wirehaired Pointers is due to a base substitution in exon 28 of the VWF gene, resulting in an amino-acid substitution. 9615
OMIA:001511 "In a conference paper, Denholm et al. (2014) reported that ""The causal mutation in CA was identified as a large (~58 kilobase pair) deletion affecting the ADAMTSL3 gene on bovine chromosome 21.""" In a conference paper, Tammen et al. (2011) reported that CA was mapped to bovine chromosome 21 in a target region of ~3.4 Mb. 9913
OMIA:001867 "Sequencing of the most likely functional candidate gene in the candidate region (see Mapping section) enabled Suárez-Vega et al. (2013) to identify the causative mutation: ""a deletion of 31 bp (c.5410_5440del) in predicted exon 36 of RELN, resulting in a premature termination codon. A functional analysis of this mutation revealed decreased levels of RELN mRNA and a lack of reelin protein in the brain cortex and blood of affected lambs.""" By conducting a GWAS/homozygosity-mapping analysis on 7 affected and 33 normal Churra sheep, each genotyped with the OvineSNP50 SNP Chip (yielding 47,864 informative SNPs), Suárez-Vega et al. (2013) mapped this disorder to a 4.8Mb region on chromosome OAR4. 9940
OMIA:001502 "Nonsense mutation: c.493C>T ""at position 65,369,074 [Btau_4.0 assembly] in [exon 4 of] the CEP250 gene"" ""that encodes the centrosomal protein C-Nap1"". The mutation ""solely affects centrosome cohesion"". ""Loss of C-Nap1-mediated centriole cohesion leads to an altered cell migration phenotype"". Results and quotations from Floriot et al. (2015)." Duchesne et al. (2009) mapped this disorder to a 6 cM interval on chromosome BTA13. By homozygosity mapping of 19 animals, each genotyped with the Illumina BovineSNP50 BeadChip and each identified as recombinant in the candidate region, Floriot et al. (2015) refined the location to 2.5Mb. 9913
OMIA:000755 Kawaguchi et al. (2001) reported that the same MITF mutation that causes silver feathering in quail also causes osteopetrosis. 93934
OMIA:000628 "By sequencing the cDNA of the almost certain comparative candidate gene (based on the homologous human disorder), namely FBN1, in affected Limousin calves, Singleton et al. (2005) discovered the causal mutation in this breed to be a 3598G>A transition in exon 29, resulting in a likely substitution of a glutamic acid by lysine at position 1200 as the cause of this syndrome (Mohammad Shariflou 6/11/2006).
Hirano et al. (2012) reported a ""G>A mutation at the intron64 splicing accepter site (c.8227-1G>A)"" as being causative for Marfan disease in Japanese Black cattle. ""The mutation causes a 1-base shift of the intron64 splicing accepter site to the 3′ direction, and a 1-base deletion in processed mRNA. This 1-base deletion creates a premature termination codon, and a 125-amino acid shorter Fibrillin-1 protein is produced from the mutant mRNA.""" "The cDNA sequence of the bovine FBN1 gene was characterized and somatic-cell-hybrid mapped to syntenic group U5, which corresponds to chromosome BTA10, by Tilstra et al. (1994) (Mohammad Shariflou 6/11/2006). Thue and Buchanen (2003) confirmed this result by linkage mapping a SNP in the FBN1 gene to chromosome BTA10, ""10 cM from BM888 (LOD = 4.88) and 14 cM from INRA096 (LOD = 3.77)."" " 9913
OMIA:000383 "The molecular basis of FecB was finally resolved by three independent groups of researchers, in three separate papers published within a month of each other in 2001.
Working on New Zealand Booroola sheep, Wilson et al. (2001; published 1 April) fine-mapped FecB to a 4cM region of OVA6, and then identified a microsatellite marker (JL36) with zero recombination with FecB, homologous with HSA4q21-24. The most likely candidate gene in this region was the gene encoding the receptor for BMP-IB, i.e. the BMPR-IB gene. Sequencing of the ovine BMPR-IB gene revealed ""a point mutation (an A to G transition) at position 830 . . . This translates to a change from a glutamine (neutral/polar amino acid) to an arginine (basic amino acid) at position 249 of the protein [Q249R] . . . in the intracellular kinase signaling domain of the BMPR-IB. Glutamine is conserved at this position in most of the type I receptors.""
Working on a flock of Booroolas in France, Mulsant et al. (2001; 24 April) did their own fine-mapping and comparative mapping, also ending up with the BMPR-IB gene as the most likely comparative positional candidate. Sequencing revealed the same Q249R mutation.
Working with Booroola sheep in Edinburgh and Brazil, Souza et al. (2001; 1 May) also zeroed in on BMPR-IB as the most likely comparative positional candidate gene, and identified the same Q249R mutation. " "The first attempts to linkage-map the FecB gene involved just 18 polymorphic protein markers (Tate et al., 1992) and 11 polymorphic blood markers (Nguyen et al., 1992). In neither case was any marker linked to FecB, thus enabling the researchers to exclude regions of the as-yet unknown sheep genome in the vicinity of those markers.
The following year, still ""in the absence of any genetic map for sheep"", Montgomery et al. (1993) assembled a veritable arsenal of 137 markers: ""55 known RFLPs, 58 random sheep microsatellites and 24 random RFLP markers"". Two of the microsatellites were found to be linked to FecB, namely OarAE101 (13cM) and OarHH55 (20cM). More importantly, an RFLP in the SPP1 gene was also found to be linked to FecB (14 cM). Noting that SPP1 in humans is located on chromosome HSA4q, Montgomery et al. (1993) then examined RFLPs in other genes in that region of HSA4q, and found another HSA4q gene linked to FecB, namely EGF (26 cM). The authors concluded that the most likely location of the FecB gene in the sheep genome is between the sheep versions of SPP1 and EGF. It is an interesting sign of the then times that the actual sheep chromosome on which these markers are located had not yet been determined. Consequently, the title of the paper referred to the FecB gene having been mapped to ""a region of human chromosome 4q"". The importance of this result at that time is indicated by the paper appearing in Nature Genetics, and by the results stimulating Dr McKusick to create an entry entitled ""Fecundity gene, Booroola, of sheep, homolog of"" in the human gene catalogue OMIM (see above link to OMIM 134720).
The identity of the chromosome was revealed the next year, when Montgomery et al. (1994) used a sheepxhamster somatic cell hydrid panel to physically map the markers linked to FecB, to sheep chromosome OVA6.
The following year, Montgomery et al. (1995) reported that some fine-mapping in the FecB region had narrowed down the region to near the centromere of OVA6." 9940
OMIA:001372 "By sequencing the most likely positional functional candidate gene within the BTA20 region to which this trait had been mapped (see Mapping section), Littlejohn et al. (2014) identified a causal mutation as ""a single homozygous frameshift mutation . . . consisting of a single base deletion in exon 10 that introduces a premature stop codon (p.Leu462*) and loss of 120 C-terminal amino acids from the long isoform of the receptor (ss1067289408; chr20:39136558GC>G""." "From a genome scan with microsatellite markers, Mariasegaram et al. (2007) mapped this locus to a region of chromosome BTA20. Using a 50k SNP chip, Flori et al. (2012) refined this region to just one positional candidate gene, namely ""Retinoic Acid induced 14 gene (RAI14 or NORPEG)"". Huson et al. (2014) narrowed this region even further, to ""a 0.8 Mb (37.7-38.5 Mb) consensus region for the SLICK locus on BTA20 in which contains SKP2 and SPEF2 as possible candidate genes"". From various lines of evidence, the authors concluded that there are ""potentially two mutations, one common to Senepol and Romosinuano and another in Carora, effecting genes contained within our refined location for the SLICK locus.""" 9913
OMIA:001518 "Based on a comparative positional cloning approach (the canine disorder maps to a location on the canine X chromosome that is homologous with the location of the same disorder (RP3) in humans, which is due to mutations in the RPGR gene), Zhang et al. (2002) identified a ""a two-nucleotide deletion (delGA) in 1084–1085"" in the canine RPGR gene as a causal mutation for a form of X-linked PRA they call XPRA2. The authors noted that this deletion ""results in a frameshift that significantly changes the deduced peptide sequence, causing an increased isoelectric point (4.30 versus 4.01), and leads to the inclusion of 34 additional basic residues before prematurely terminating translation 71 amino acids downstream""." 9615
OMIA:002017 "Kuehn et al. (2016): ""A 4 base-pair insertion was identified in exon 8 [at chrB3: 120995236] of LTBP2 in affected individuals that generates a frame shift that completely alters the downstream open reading frame and eliminates functional domains""." "As reported by Kuehn et al. (2016): ""Using a candidate gene approach, significant linkage was established on cat chromosome B3 (LOD 18.38, θ = 0.00) using tightly linked short tandem repeat (STR) loci to the candidate gene, LTBP2.""" 9685
OMIA:000296 "In a landmark paper, Dorshorst et al. (2015) showed that ""the two Duplex-comb alleles, V-shaped (D*V) and Buttercup (D*C), are both associated with a 20 Kb tandem duplication containing several conserved putative regulatory elements located 200 Kb upstream of the eomesodermin gene (EOMES). EOMES is a T-box transcription factor that is involved in mesoderm specification during gastrulation."" The authors note that ""The confinement of the ectopic expression of EOMES to the ectoderm is in stark contrast to the causal mechanisms underlying the two other major comb loci in the chicken (Rosecomb and Pea-comb) in which the transcription factors MNR2 and SOX5 are ectopically expressed strictly in the mesenchyme"". Headon (2015) provides a very informative commentary on this discovery." "The first data showing linkage of duplex comb to any other trait (in this case, polydactyly) were provided by Sererbrovsky and Petrov (1930). Duplex comb was allocated to a new (fifth) linkage group (group E) initially comprising duplex and multiple spurs (OMIA 000671-9031), by Hutt (1941), who was not aware of the results of Sererbrovsky and Petrov (1930). Additional data on this linkage group, including new loci, were provided by Warren (1941), and Hutt and Mueller (1943). The trait was included in Warren (1949)'s classic chicken linkage map. Dorshorst et al. (2010) were the first to physically map this trait, in the ""33.6–39.8 Mb region of chromosome [GGA]2"". Wragg et al. (2012) narrowed this location to 38.55–38.89 Mb on chromosome GGA2." 9031
OMIA:000702 "By cloning and sequencing a very likely candidate gene (based on prior physiological and biochemical studies, reinforced by strong linkage between the disorder and that gene), Primorac et al. (1994) demonstrated ""A stop codon . . . at codon 1513, which is located in the eighth repeat of the chondroitin sulfate 2 domain of the large tenth exon [of the avian aggrecan gene].""" 9031
OMIA:000545 The disorder is due to a nonsense mutation in codon 114 of the gene for neurofilament protein, light polypeptide (NEFL), resulting in no functional NEFL protein (Ohara et al., 1993). 93934
OMIA:002114 Markey et al. (2010): 5:g.27505486delTGTGCCCA, c.334delTGTGCCCA, p.Met93AsnfsX14 (as gleaned from McClure and McClure, 2016) 9913
OMIA:000248 By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Benson et al. (2003) showed that the causative mutation is a single base pair insertion in exon 20 of AP3 beta gene (AP3B1), which encodes the beta 3A subunit of adaptor protein complex 3 (AP3). This causes a frame shift in the amino acid code, and ultimately premature termination of AP3 mRNA. Affected animals are homozygous for the mutation, have no AP3 beta mRNA, while carriers have half the expected amount (Benson et al., 2003). CFA (3) 9615
OMIA:001801 9940
OMIA:001937 "By sequencing likely candidate genes in 44 cortisol-secreting adrenocortical tumors, Kool et al. (2013) reported ""Approximately one-third of all ATs harbored an activating mutation of GNAS. Missense mutations, known to result in constitutive activation, were present in codon 201 in 11 ATs, in codon 203 (1 AT), and in codon 227 (3 ATs). No functional mutations were found in MC2R and PRKAR1A."" The authors went on to state ""To the best of our knowledge, this is the first report of potentially causative mutations in canine cortisol-secreting ATs.""" 9615
OMIA:001703 A study of genes known to cause chondrodysplasia in humans, combined with comparative mapping and studies with knockout mice all suggested fibroblast growth factor receptor 3 as a candidate gene. Starting with single-strand conformational polymorphism (SSCP) studies, and ending with sequencing, Beever et al. (1998) identified a single base substitution causing a non-conservative amino-acid substitution as the causative mutation. Full details of the mutation were reported by Beever et al. (2006). A genome scan in two carrier X carrier families localised the gene to the distal end of chromosome 6 (Cockett et al., 1999) 9940
OMIA:001524 9615
OMIA:001580 Lyons (2010) included this trait in a list of traits for which a DNA test is available, stating the cause as a deletion/insertion in the KIT gene (c.1035_1036delinsCA). She cited a paper by Gandolfi B, Bach L, Beresford L, et al, which has not yet been published. 9685
OMIA:000565 "By adopting a comparative positional cloning approach, having established AMN as a very strong comparative positional candidate gene (see Mapping section above), He et al. (2005) showed that the causative mutation in Giant Schnauzers is an ""in-frame deletion of 33 nucleotides in exon 10 of AMN . . . [namely] c.1113_1145del""; the causative mutation in Australian shepherds is ""a G>A transition at position 3 of the cDNA sequence [of AMN] (c.3G>A), thereby disrupting the Kozak consensus sequence for translation initiation""." Using a whole-genome scan with microsatellite markers in a pedigree of 88 dogs of known disorder phenotype, He et al. (2003) mapped this disorder to a 4Mb interval on chromosome CFA8. The authors noted that this region of CFA8 has conserved synteny with the region of chromosome HSA14q that harbours a very strong comparative candidate gene, namely AMN (amnionless), mutations in which cause the same clinical disorder in humans. 9615
OMIA:001579 "Ren et al. (2011) reported a G32E missense mutation in PPARD as the basis of the major QTL for ear size on chromosome SSC7.
" "Major QTL for this trait were mapped on chromosomes SSC5 and SSC7 by Wei et al. (2007) and Ma et al. (2009).
Zhang et al. (2014) narrowed the QTL on SSC5 to a 450kb region containing two functional candidate genes, namely LEMD3 and WIF1. " 9825
OMIA:000901 Duplication of a 577kb region on chromosome CFA9 (from 11,016,965 to 11,593,933; CanFam2 genome assembly) containing SOX9, a gene with a central involvement in sex determination (Rossi et al., 2014). Note that the location of this duplication is not consistent with the CFA29 map location reported by Pujar et al. (2007). "A genome-wide linkage screen localized the sex-reversal locus to a 5.4-Mb region on CFA29 in a study on affected American Cocker Spaniels (Pujar et al., 2007).
A Robertsonian translocation involving CFA23 was identified in one Bernese mountain dog (Switonski et al., 2011)." 9615
OMIA:000837 "Giesen et al. (2009) reported an affected cat with two mutations in the CYP27B1 gene: a missense mutation (Val75Met) and a single base deletion (731delG), the latter of which is more likely to be the cause of the clinical signs. Grahn et al. (2012) reported a second causative mutation also in exon 4 of the same gene: ""exon 4 G637T nonsense mutation results in a premature protein truncation, changing a glutamic acid to a stop codon, E213X, likely causing the clinical presentation of rickets.""" 9685
OMIA:000939 The causative mutation is a ~140 kb deletion removing exons 4-6 of LIX1 and all except exon 1 of LNPEP (Fyfe et al., 2006). FCA (A1q) 9685
OMIA:001712 "By sequencing some of the comparative positional candidate keratin genes described in the Mapping section, Gandolfi et al. (2013) identified the causal mutation as a c.445-1G>C SNP which ""likely disrupts the highly conserved acceptor splicing site of intron one."" They also reported that ""Sequence of the complete RNA transcript revealed that an alternative downstream acceptor was employed. The new alternative acceptor site was found within the first 18 bp of exon 2 (r.445_464del), thus an alternative splice site was recognized at base 18 in the modified exon 2. In silico translation predicted the loss of 6 amino acids in the KRT71 protein.""" By conducting a GWAS on 9 curly-coated Selkirk Rex and 29 control cats (comprising 6 Selkirk Rex straight-haired, 5 Persians, and 18 Scottish Folds), each genotyped with the Illumina Infinium Feline 63 K iSelect SNP chip (yielding 52,553 informative SNPs), Gandolfi et al. (2013) mapped the curly-coat trait to a 716kb region on cat chromosome B4, namely from 81,264,280 to 81,980,475. A ~600kb haplotype within this region was shown (from the feline-human comparative map) to contain 26 (candidate) keratin genes. 9685
OMIA:000209 Haase et al. (2015): a missense variant in exon 4 (c.662A>C; p.Tyr221Ser) 9793
OMIA:001403 9615
OMIA:001230 Using a comparative candidate-gene strategy (based on the homologous disorder in other species), Kawakura et al. (1996) showed that the SRY gene was absent in three XY female Japanese cattle. The authors concluded that these cases of sex reversal were due to a deletion of the SRY gene. 9913
OMIA:000078 "Sequencing of the GRM1 positional candidate gene by Zeng et al. (2011) identified the causal mutation as ""a 62-bp truncated retrotransposon insert in exon 8""." "By conducting a case-control GWAS on 12 affected and 12 control Coton de Tulear dogs, each genotyped with the Illumina ""CanineHD Whole-genome genotyping kit"", Zeng et al. (2011) mapped this disorder to a region on chromosome CFA1. Subsequent homozygosity mapping narrowed the region to ""a 713 kb region that contained part or all of 4 annotated genes: FBXO30, SHPRH, GRM1, and RAB32""." 9615
OMIA:002102 "Via a GWAS involving 172 control and 18 affected Holstein-Friesians, each genotyped with the Illumina BovineSNP50 BeadChip (yielding 44,952 informative SNPs), Hollman et al. (2017) mapped this disorder to a region of ""bovine chromosome 8 (BTA8) spanning from 57.3 to 65.3 Mb"", and ""The SNP with the highest -log10(p) = 9.17 (BTB-00352779) was located at position 60,990,733 (NCBI UMD3.1.1)"". " 9913
OMIA:000396 By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Skelly et al. (1996) identified a 14-bp deletion at the 3' end of exon 1 of the canine gene for alpha-L-fucosidase, in dogs affected with fucosidosis, causing a frameshift which results in 25 novel codons followed by two premature stop codons. Using the same strategy, Occhiodora and Anson (1996) reported the same mutation in an Australian colony of the same breed. CFA2 9615
OMIA:001973 Metzger et al. (2015) identified a single nucleotide sustitution in exon 8, c.1250G>A, as the most likely causative variant. This variant alters the encoded amino acid seqeunce (p.Arg417Gln). However, the variant predominantly leads to aberrant splicing as it generates a cryptic splice acceptor site within exon 8. Metzger et al. (2015) identified a transcript lacking 54 nucleotides from the beginning of exon 8 in affected dogs. Western blot analysis demonstrated that the SLC27A4 protein is only expressed at very low levels in the skin of affected dogs compared to control dogs. The disease locus was mapped to chromosome 9 by a genome-wide association study (GWAS) using 9 affected and 13 control dogs and illumina canine_HD SNP chip genotypes (Metzger et al. 2015). The most significantly associated markers were located in the 740 kb interval from 54,031,320 to 54,772,131 (CanFam3.1). 9615
OMIA:001765 "Using a comparative-candidate gene approach (based on similar clinical signs in humans, rats and horses), Lühken et al. (2012) reported ""a deletion of about 110 kb on sheep chromosome [OVA]10, comprising the entire EDNRB gene"" as being responsible for this disorder. Interestingly, they noted that this region corresponds to a fragile site in the ovine genome (see OMIA 000392-9940). Pauciullo et al. (2013) confirmed the result of Lühken et al. (2012), and showed that the EDNRB gene itself is approximately 21kb in length. The ovine EDNRB gene is now called ETBR." "Following on from their discovery of a deletion of EDNRB as being causal of megacolon in sheep, Pauciullo et al. (2013) physically mapped the ovine EDNRB gene to chromosome OAR10q22, using ""R-banding and propidium iodide-staining fluorescent in situ hybridization"". This confirmed the initial mapping of the same gene by Iannuzzi et al. (2001). " 9940
OMIA:001899 After having established the X-chromosomal inheritance the genome of an affected crossbred mare was re-sequenced at 19x coverage (Towers et al. 2013). The analysis of the sequence data yielded 557 non-synonymous variants on the X-chromosome with respect to the genome reference sequence of an unaffected Thoroughbred mare. Exclusion of variants that were also present in the genome sequences of 44 control horses from 11 breeds resulted in a reduced list of 33 private non-synonymous X-chromosomal variants in the IP affected mare. By visual inspection of this list and based on the knowledge of the human condition the authors concluded that a nonsense variant in the IKBKG gene is the most likely causative variant for IP in the investigated horse family. The variant is c.184C>T and predicted to result in p.Arg62*. The same variant at the homologous position in the human IKBKG gene had been previously reported in a human IP patient. The variant also showed perfect co-segregation with IP in the horse family and was present in all 3 available cases (Towers et al. 2013). Pedigree analysis of a horse family segregating for IP clearly indicated the X-chromosomal dominant inheritance (Towers et al. 2013). 9796
OMIA:000487 "Ducro et al. (2015) in Friesian horses: ""nonsense mutation XM_001491545 c.1423C>T corresponding to XP_001491595 p.Gln475* in B3GALNT2 (1:75,859,296-75,909,376)""" 9796
OMIA:002084 "By comparing the whole-genome sequence of two affected Soft-Coated Wheaten Terriers and ""100 control canid whole genome sequences"", Kolicheski et al. (2016) identified the likely causal mutation as a missense SNP (c.398C>T; p.T133I) in the PIGN gene. " 9615
OMIA:001574 "Verfuurden et al. (2011): c.2893G>T; p.Glu965* in Frisian Water Dog
" 9615
OMIA:000437 9913
OMIA:001424 "By cloning and sequencing a very likely candidate gene (based on evidence of the lack of beta-casein in milk of affected animals), Pursuy et al. (1999) reported ""a one-nucleotide deletion in the 5' end of exon 7 [of CSN2], which introduces a premature stop codon. The open reading frame of allele CSN2O encodes a shortened polypeptide of 72 amino acids, compared to 223 amino acids for caprine pre beta-casein A."". Cosenza et al. (2007) reported a ""SNP in the goat CSN2 promoter region (AJ011018:g.1311T>C), which is associated with the absence of beta-casein in the milk"". " 9925
OMIA:001494 9103
OMIA:001455 "Sequencing of positional candidate genes in the CFA5 region (see Mapping section) by Wiik et al. (2008) ""identified a 180-bp deletion in exon/intron 5 of NPHP4 (nephronophthisis 4, also known as nephroretinin)"".
Palánová et al. (2014) ""analyzed all varieties of Dachshunds from the Czech Republic and five other dog breeds and found that the deletion in the NPHP4 (in heterozygous state) is present not only in standard-, but also in miniature wire-haired Dachshunds, but not in other varieties of Dachshunds or in other breeds.""" "Wiik et al. (2008) conducted a GWAS on 13 affected and 13 control Standard Wire-Haired Dachshunds, each genotyped with the Affymetrix version 2 Dog SNP (yielding 49,663 informative SNPs for analysis). They reporte that ""For the first time, we use genome-wide association-based Sibling Transmission Disequilibrium Test (sibTDT) analysis of only 13 discordant sib-pairs to identify a single significantly associated 6.5-Mb region (PrawTDT = 4.8 × 10−5, PgenomeTDT = 6 × 10−4) on canine chromosome 5, containing more than 70 genes"". " 9615
OMIA:001444 "The causative mutation of cmr1 in the Great Pyrenees, the English mastiff and the bullmastiff is a C to T mutation that generates a premature stop codon: c.73C>T; p.Arg25Ter (Guziewicz et al., 2007).
Gornik et al. (2014) reported this same causal mutation in a Boerboel." CFA18 9615
OMIA:001427 "By sequencing a very likely comparative candidate gene (namely GM2A, based on the homologous disorder in humans), Martin et al. (2005) were able to report that ""a deletion of 4 base pairs was identified as the causative mutation, resulting in alteration of 21 amino acids at the C terminus of the GM2 activator protein"". According to variant nomenclature as of the year 2013, this corresponds to c.516_519delGGTC or p.V173Sfs*17." 9685
OMIA:001575 Downs et al. (2013) reported the causal mutation of this type of progressive retinal atrophy as being a frameshift mutation (c.3149_3150insC) in the gene C2orf71 (now called C17H2orf71). However, this mutation does not account for all cases, indicating that there are more causal mutations yet to be discovered. Using a GWAS on 16 cases and 22 controls in the Gordon Setter breed, Downs et al. (2013) mapped this disorder to 3.2 Mb region on chromosome CFA17. 9615
OMIA:001678 """2.4 kb deletion encompassing the first exon of the LAMC2 gene"" (Murgiano et al., 2015)" 9913
OMIA:000665 "By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Cavanagh et al. (1995) showed that this disorder in goats is due a nonsense mutation (""changing a C to T in codon 102 of the 559-amino-acid G6S coding sequence"") in the 5' region of the caprine gene for N-acetylglucosamine-6-sulphatase (GNS)." 9925
OMIA:001469 "Awasthi Mishra et al. (2017) reported a likely causal variant for this classic phene: ""The belt-associated variant was a copy number variant (CNV) involving the quadruplication of a 6 kb non-coding sequence located approximately 16 kb upstream of the TWIST2 gene. Increased copy numbers at this CNV were strongly associated with the belt phenotype in a cohort of 333 cases and 1322 controls. We hypothesized that the CNV causes aberrant expression of TWIST2 during neural crest development, which might negatively affect melanoblasts. Functional studies showed that ectopic expression of bovine TWIST2 in neural crest in transgenic zebrafish led to a decrease in melanocyte numbers.""" Drögemüller et al. (2009) mapped this locus in Brown Swiss cattle to a 922 kb region on chromosome BTA3. In a second paper in the same year, the authors reported narrowing down the candidate region to 336 kb. No compelling functional candidate gene could be identified in the interval. 9913
OMIA:001675 Oh et al (2017); '2 base pair (bp) deletion in exon 13 (c.1282delCT) . . . p.L428*' 61379
OMIA:000175 9796
OMIA:001776 "On the strength of the clinical evidence implying a deficiency of the enzyme dihydropyrimidinase (see section on Clinical features), Chang et al. (2012) used the direct candidate gene approach and sequenced the DPYS gene encoding this enzyme, in the affected cat, showing that ""the cat was homozygous for the missense mutation c.1303G>A (p.G435R) in exon 8, which corresponds to a known mutation in a human patient with DHP deficiency."" " 9685
OMIA:001953 Splicing variant 10 bp upstream of the intron1/exon 2 boundary (c211-10C>G) at position 79,814,520 (Bos taurus assembly: BosTau6/UMD3), leading to skipping of exon 2 (Sartelet et al., 2015) "By conducting a GWAS on 15 affected calves and 125 normal bulls, each genotyped (in effect) for 34,368 SNPs, Sartelet et al. (2015) mapped this disorder to a 2.2 MB region of bovine chromosome BTA10: ""chr10:78,424,435-80,602,211 bp; Bos taurus assembly: BosTau6/UMD3""." 9913
OMIA:001978 "Wiedemar et al. (2015) reported a likely causal mutation: ""a SNP replacing a thymine by a guanine on bovine chromosome 5 at bp-position 65,787,153. It was clearly identified as a de novo mutation as it was absent in both parents, but present in the calf . . . . Interestingly, this SNP situated in exon 13 of the myosin binding protein C slow type (MYBPC1) gene at position 885 of the open reading frame (c.885T>G) is predicted to lead to an amino acid exchange from leucine to arginine of the encoded MYBPC1 protein sequence at position 295 (p.Leu295Arg)""." 9913
OMIA:000042 "The causal mutation for this disorder was identified via a comparative positional cloning approach (as described in the Mapping section above, the locus was mapped to a region of the chicken Z chromosome (GGAZ) that is homologous to human HSA9q22.3-32, which includes the gene ABCA1, mutations in which cause Tangier disease, which is similar to this chicken disorder). Sequencing of the chicken ABCA1 gene by Attie et al. (2002) revealed the causal mutation as ""a missense mutation [G265A] near the N-terminus of the protein (E89K)"". The authors reported that ""This alteration is a non-conservative amino acid substitution at a residue that is conserved in the ABCA1 gene between human, mouse, chicken, and Takifugu rubripes (“fugu”)""." Bitgood (1985) and Bitgood (1988) reported loose linkage of the WHAM locus to loci B and ID on the chicken Z chromosome. Fridolfsson et al. (1998) showed that this region contains the genes ALDOB and MUSK, which were physically mapped to Zq1.5-1.6, which is homologous with human HSA9q22.3–q32. 9031
OMIA:000807 By sequencing the candidate gene PKD1 in two affected and two non-affected Bull Terriers, Gharahkhani et al. (2011) identified a missense mutation in exon 29 that was subsequently shown to be completely associated with the disorder in 47 affected and 102 non-affected dogs of the same breed. 9615
OMIA:000323 By sequencing the more likely of the two positional candidate genes (see Mapping section), Drögemüller et al. (2008) showed that this disorder is due to a 7-bp tandem duplication in exon 1 of FOXI3, a member of the family of forkhead box transcription factor genes. This gene was previously unknown to contribute to the development of ectodermal structures. "By conducting a GWAS on ""20 hairless and 19 coated Chinese Crested dogs"", each of which had been genotyped with the Affymetrix v2 SNP chip (yielding 12,353 informative SNPs) Drögemüller et al. (2008) highlighted a single SNP on chromosome CFA17. Fine-mapping reduced the candidate region to ""a 102-kb interval between positions 41,045,331 and 41,147,100 on CFA 17"", containing only two predicted genes." 9615
OMIA:000101 "Holopainen et al. (2017) ""combined SNP-based homozygosity mapping of two ARDS-affected Dalmatian dogs and whole genome sequencing of one affected dog to identify a case-specific homozygous nonsense variant, c.31C>T; p.R11* in the ANLN gene. Subsequent analysis of the variant in a total cohort of 188 Dalmatians, including seven cases, indicated complete segregation of the variant with the disease and confirmed an autosomal recessive mode of inheritance"". " 9615
OMIA:001342 In what must be a sign of the times, Karageorgos et al. (2007) documented the first reported occurrence of this disorder in cattle and, in the same paper, also reported its molecular basis; in this case a missense mutation E452K (c.1354G>A) in the gene for alpha-N-acetylglucosaminidase (NAGLU). 9913
OMIA:000214 """Whole genome sequencing [by Menzi et al., 2016] identified a 1 Mb copy number variant (CNV) harboring 5 genes including EDNRA. The analysis of 358 Boer goats revealed 3 alleles with one, two, and three copies of this CNV. The copy number is correlated with the degree of white spotting in goats."" The duplicated EDNRA copies contain a missense variant (p.Tyr129His) predicted to increase the affinity of the encoded mutant receptor for endothelin 3. Menzi et al. proposed a hypothesis whereby ectopic overexpression of a mutant EDNRA scavenges EDN3 required for EDNRB signaling and normal melanocyte development and thus likely leads to an absence of melanocytes in the non-pigmented body areas of Boer goats." "Menzi et al. (2016) ""mapped the locus causing this white spotting phenotype to chromosome 17 by genome wide association""." 9925
OMIA:001576 "Zhang et al. (2014) reported the same molecular basis of colour-sidedness in yaks as in cattle, namely (as reported by Durkin et al., 2012) ""colour sidedness is determined by a first allele on chromosome 29 (Cs(29)), which results from the translocation of a 492-kilobase chromosome 6 segment encompassing KIT to chromosome 29, and a second allele on chromosome 6 (Cs(6)), derived from the first by repatriation of fused 575-kilobase chromosome 6 and 29 sequences to the KIT locus"" [see OMIA 001576-9913]" 30521
OMIA:000733 "From studying the exon 11 missense Silver mutation in PMEL17 (OMIA001438-9796) in five affected ponies, Komáromy et al. (2011) concluded ""Our case series supports the notion that the (still unknown) MCOA [mutation] and the PMEL17 (Silver) [mutation] are the same, or at least overlap on ECA6q23"".
A month later, Andersson, Axelsson et al. (2011) confirmed the above result, by showing that in Icelandic horses the disorder segregates with the missense mutation in exon 11 of PMEL17 (Arg618Cys) that causes Silver coat colour (OMIA001438-9796), but they did report three horses heterozygous for the PMEL17 mutation that did not show any clinical signs, suggesting incomplete penetrance.
Andersson et al. (2013) deep-sequenced the 208kb candidate region (see Mapping section above) in ""five homozygous MCOA horses from three different breeds [American Miniature, Icelandic Horse, Rocky Mountain Horse], one horse with the heterozygous Cyst phenotype [American Miniature] and four unaffected controls [American Miniature, Rocky Mountain Horse]"". After excluding all SNPs and indels that did not exactly match the inheritance of the disorder in the ten sequenced horses, only two SNPs remained, both in what they called the PMEL gene (one in a nonconserved intronic region, and the other a missence mutation (Arg625Cys), which is actually the same as the silver mutation (Arg618Cys) studied by Andersson, Axelsson et al. (2011). Andersson et al. (2013) concluded that ""the missense mutation is causative and has pleiotrophic effect, causing both the horse silver coat color and MCOA syndrome""." Andersson et al. (2008) mapped this disorder to a 4.9 Mb region on chromsome ECA6q containing the PMEL17 gene, an exon 11 missense mutation in which causes Silver coat colour (OMIA001438-9796). Furthermore, they reported that the actual missense mutation showed complete linkage with the disorder. The candidate region was narrowed to a 208kb region by Andersson, Lyberg et al. (2011). 9796
OMIA:002015 "Hytönen et al. (2016): the likely causal mutation in Border Collies is a ""non-synonymous [missense] homozygous variant, c.899C>T, in the FAM20C gene. This leads to a missense change, p.A300V, in a highly conserved position in the kinase domain of the FAM20C protein""." 9615
OMIA:000344 9031
OMIA:001348 9544
OMIA:001805 "Three of the ten genes in the candidate region described in the Mapping section above are involved in enamel development. Mutations in one of these three positional candidate genes (ENAM) are causal in one form of human amelogenesis imperfecta. Gandolfi et al. (2013) therefore chose to sequence the canine ENAM gene in three affecteds and one normal Italian Greyhound. Sequencing revealed the likely causal mutation as ""a 5-bp deletion . . . , c.1991_1995delTTTCC, in exon 10, resulting in a frameshift and premature termination codon at position 668 (p.Phe665Argfs*3) of the protein""." After genotyping each of 22 affected and 49 normal Italian Grehounds with the Illumina CanineHD Genotyping BeadChip, which contains 173,662 SNPs, Gandolfi et al. (2013) conducted a GWAS which mapped the disorder to a 1.84 Mb region of chromosome CFA15, which contains 10 genes. 9615
OMIA:001569 9031
OMIA:001454 9615
OMIA:001465 "Deletion: a 23,363 bp deletion ""encompasses the entirety of the ISG15 ubiquitin-like modifier (ISG15) gene . . . one or both of the 5' regulatory region of the hairy and enhancer split 4 (HES4) and of the agrin (AGRN) gene and of the first two exons of the AGRN gene"" (Beever and Marron, 2011)" 9913
OMIA:000508 The molecular basis of this disorder has not been published, but a DNA test for the disorder is included in the OFA's list at http://www.offa.org/dna_alltest.html, which directs enquiries to the Goldstein Molecular and Genetics Laboratory at Cornell University (http://www.vet.cornell.edu/faculty/Goldstein/) 9615
OMIA:000202 Galante Rocha de Vasconcelos et al. (2017): c.64C>T; p.R22* 9515
OMIA:001587 Trepanier et al. (1997) showed that all dogs, and other canids, lack both NAT1 and NAT2 genes, and hence compleley lack the enzyme cytosolic N-acetyltransferase (NAT). 9615
OMIA:001436 9825
OMIA:001962 "Small deletion: ""c.843delT is predicted to cause a frame shift and premature stop codon resulting in a truncated protein, MFSD8:p.F282Lfs13*, missing its 239 C-terminal amino acids"" in the Chinese Crested breed (Guo et al., 2015).
Faller et al. (2016) demonstrated that the same genetic variant is also present in Chihuahuas with neuronal ceroid lipofuscinosis 7.
Karli et al. (2016) reported that ""the MFSD8:c.843delT variant is also present [and causal] in Chihuahuas without official registrations.""
Ashwini et al. (2016) also reported the same likely causal mutation in Chihuahuas." 9615
OMIA:001001 "Being aware of an earlier unpublished discovery by M.K. Boudreaux of a missense mutation in the TUBB1 gene (encoding beta1-tubulin) in several King Charles Cavalier Spaniels (CKCS) with macrothrombocytopenia, Davis et al. (2008) genotyped for this mutation in 100 CKCS dogs and 52 dogs from other breeds, for most of which platelet numbers and volume were recorded. They confirmed that a ""missense mutation (c.745 G>A) in the gene encoding beta1-tubulin, predicted to result in the substitution of an asparagine for aspartic acid (D249N), correlated with the macrothrombocytopenia observed"" (with thanks to Dr. Mario Van Poucke for identifying an error in an earlier version of this entry). Only one of the dogs from other breeds (a Labrador Retriever) had the same mutation (as a heterozygote).
Gelain et al. (2014) reported a different missense mutation (c.5G>A; p.R2H) in the same gene (TUBB1) as the likely cause of a very similar disorder in Norfolk and Cairn Terriers." 9615
OMIA:001771 7091
OMIA:000218 "By a neat bit of detective work that makes use of between-breed variation in linkage disequilibrium in tracking down mutations that are common to several breeds, Parker et al. (2007) showed that Collie Eye Anomaly in four breeds is due to a deletion of 7.8kb in the NHEJ1 gene.
A warning that the causality of this mutant may not be as straightforward as initially thought, was provided by Fredholm et al. (2016) who reported that "" the deletion in NHEJ1 is not predictive for CH [choroidal hypoplasia] in the Danish Rough Collie population, whereas the clinical and genetic diagnosis is in accordance with each other in the Shetland Sheepdog population. Based on these results, it can be concluded that the intronic deletion in NHEJ1 is not the causative mutation but, rather, a marker linked to the locus underlying the trait in some populations but linked to both the wild-type and CH-causing locus in most dogs in the Danish Rough Collie population.""" CFA37 9615
OMIA:001980 "Immunohistochemistry on skin biospies of affected dogs demonstrated a lack of NIPAL4 (also termed ichthyin) protein expression (Mauldin et al. 2015). The authors identified a 338 bp SINE insertion upstream of the NIPAL4 gene in affected American Bulldogs, which represents a strongly associated marker, but not the causative variant (Margret Casal, personal communication).
By sequencing ""six exons of NIPAL4 gene from DNA obtained from an ARCI affected dog, and its clinically healthy parents and littermates"", Casal et al. (2017) identified ""a homozygous single base deletion (CanFam3.1 canine reference genome sequence NC_06586.3 g.52737379del), the 157th base (cytosine) in exon 6 of NIPAL4 as the most likely causative variant in affected dogs. This frameshift deletion results in a premature stop codon producing a truncated and defective NIPAL4 (ichthyin) protein of 248 amino acids instead of the wild-type length of 404."" " Linkage analysis with microsatellite markers derived from likely candidate genes demonstrated linkage of the ichthyosis phenotype with the NIPAL4 gene (Mauldin et al. 2015). 9615
OMIA:000420 By cloning and sequencing a very likely comparative candidate gene (based on biochemical and histopathological evidence relating to the homologous disorder in other species), Ward et al. (2004) showed that this disorder in American Quarter horses is due to a 102C>A base substitution in exon 1 of the GBE1 gene encoding glycogen branching enzyme, resulting in a Y34X nonsense mutation. 9796
OMIA:001674 "Sequencing of a likely candidate gene (PDE6B) in the candidate block (see Mapping section) enabled Goldstein et al. (2013) to identify the causal mutation to be ""a three-bases-deletion . . . in exon 21 of the gene in the affected dogs (c.2404-2406del, CFA3: 94,574,289-94,574,291), in-frame with the protein . . . . This mutation would result in a deletion of the amino acid asparagine at position 802 of the protein (p.802del)""." By conducting a GWAS on 17 affected and 18 control dogs from a colony of American Staffordshire Terriers segregating the disorder, each genotyped for 173,662 SNPs on the Illumina HD Canine SNP chip, Goldstein et al. (2013) mapped crd1 to a region of chromosome CFA3. Homozygosity mapping identified a 1.05 Mb candidate block at the telomeric end of CFA3. 9615
OMIA:001870 "By sequencing one affected, one carrier and one normal dog from the POAG Beagle colony, for the entire 4MB candidate region described in the Mapping section above, Kuchtey et al. (2011) identified the causal mutation as a ""56097365 G->A variant [Gly661Arg] . . . within exon 17 of ADAMTS10, a member of the disintegrin and metalloproteinase with thrombospondin motifs family of secreted proteases involved in formation of the extracellular matrix"". The authors noted that ""glycine at position 661 is completely conserved in 38 vertebrate species"". By genotyping Beagle dogs not belonging to the POAG Beagle colony, Kuchtey et al. (2013) provided strong supportive evidence for the 56097365 G->A variant [Gly661Arg] being a causal mutant of POAG in this breed.
Kanemaki et al. (2013) provided evidence that variants in ADAMTS10 are not causal for this disorder in Shiba-Inus and Shih-Tzus, but that variants in SRBD1 (another comparative candidate gene) ""play an important role in glaucoma pathology in both Shiba-Inus and Shih-Tzus"".
Ahonen et al. (2014) reported a different likely causal mutation in Norwegian Elkhound: ""A fully segregating missense mutation (p.A387T) in exon 9 was found in 14 cases and 572 unaffected NEs (pFisher = 3.5×10-27) with a high carrier frequency (25.3%). The mutation interrupts a highly conserved residue in the metalloprotease domain of ADAMTS10, likely affecting its functional capacity""." "By genotyping ""19 affected and 10 carrier dogs from the POAG Beagle colony using version 2 of the Affymetrix Canine Genome SNP array"", Kuchtey et al. (2011) conducted a GWAS that mapped the POAG locus to a 4Mb region on chromosome CFA20. " 9615
OMIA:000938 "By sequencing the most likely of the genes (based on clinical signs in mice that are mutant for this gene) in the candidate region on CFA8, namely NKX2-8, Safra et al. (2013) identified a causal mutation as ""a G to AA frameshift mutation within exon 2 of the gene, resulting in a premature stop codon that is predicted to produce a truncated protein"" (p.A150VfsX1). Importantly, Safra et al. (2013) then sequenced the ""exons of NKX2-8 . . . in human patients with spina bifida and rare variants (rs61755040 and rs10135525) were found to be significantly over-represented (p = 0.036). This is the first documentation of a potential role for NKX2-8 in the etiology of [human] NTDs, made possible by investigating the molecular basis of naturally occurring mutations in dogs.""" In a GWAS on just 4 unrelated affected Weimaraners and 96 controls from the same breed were each genotyped with the Illumina 170K CanineHD BeadChip (yielding 114,775 informative SNPs for analysis), Safra et al. (2013) used GWAS to identified a 1.5Mb candidate region on chromosome CFA8 that includes 18 genes. 9615
OMIA:001442 "By comparing sequence in the candidate region (see Mapping section above) of a carrier bull with the bovine reference sequence, Akiyama et al. (2013) identified a causal mutation as ""a nucleotide substitution of C to T in exon 4 of the glial cell line derived neurotrophic factor family receptor alpha 1 (GFRΑ1) gene result[ing] in a Q144X mutation""." "Via a genome scan involving 258 microsatellites, Masoudi et al. (2007) mapped this disorder to the middle of chromosome BTA26. Subsequent fine-mapping narrowed down the candidate region to ""a 3.5-Mb interval on BTA26 between BM4505 and MOK2602"" (Masoudi et al., 2007)." 9913
OMIA:002065 "Zampieri et al. (2014): ""intronic mutation located 5 nt downstream of the canonical donor splice site of exon 1""; c.82+5G>A; ""the mutation affects the splicing process causing the retention of 105 bp of intron 1 in the mature mRNA, which would lead to the in frame insertion of 35 amino acids between residues 28 and 29 of the NPC2 protein (p.G28_S29ins35).""" 9685
OMIA:001970 "Wiedmer et al. (2015) performed whole genome sequencing of a POANV affected Alaskan Husky. An initial automated small-scale variant analysis of the sequence data did not reveal a plausible candidate variant. Wiedmer et al. then visually inspected the short read alignments of the affected Alaskan Husky in the critical interval on chromosome 19 and identified a 218 bp SINE insertion into exon 7 of the RAB3GAP1 gene, (RAB3GAP1:c.614_615insLN864704:g.123_340). The SINE insertion was perfectly associated with the POANV phenotype in a cohort of 43 Alaskan Huskies, and it was absent from 541 control dogs of 68 other breeds. Wiedmer et al. (2015) observed that the SINE insertion leads to aberrant splicing. The mutant allele predominantly gives rise to a transcript that uses an internal splice acceptor within the SINE insertion. This mutant transcript is predicted to encode a protein, in which 39 wildtype amino acids are replaced by 46 mutant amino acids. A minor amount of transcript, in which the entire exon 7 was skipped, was observed in RNA from blood cells, but not in brain.
Mhlanga-Mutangadura et al. (2016) performed whole genome sequencing at 29.3x coverage of a POANV affected Black Russian Terrier. They compared the sequence data to the genomes of 73 control dogs and identified 71 private homozygous variants in the POANV affected dog, which were predicted to alter the amino acid of a gene product. Based on a literature-based survey of the affected genes, a single base deletion in the RAB3GAP1 gene was identified as the most likely causative variant (RAB3GAP1:c.743delC). This variant was perfectly associated with the POANV phenotype in a cohort of 262 Black Russian Terriers. The variant was absent from 100 randomly selected dogs of other breeds.
" Wiedmer et al. (2015) performed linkage mapping with illumina SNP chip genotypes in a cohort of 18 Alaskan Huskies and obtained maximum LOD scores of 1.976 for five different genome segments on chromosomes 2, 11, 15, 17, and 19. The further performed homozygosity mapping in four affected Alaskan Huskies and found a single homozygous region with shared haplotypes amongt the 4 cases on chromosome 19. The combined linkage and homozygosity analysis thus defined an exact critical interval of 4,086,630 bp at chr19:36,483,638–40,570,267 (CanFam 3.1 assembly). 9615
OMIA:001918 "Encouraged by the fact that a comparative (human) candidate gene (namely FAM161A, mutations in which cause retinosis pigmentosa (RP) 28) shows conserved synteny with the candidate region identified in their GWAS (see Mapping section), Downs and Mellersch (2014) next-gen sequenced the 3.8Mb candidate region in 4 affected, 2 obligate carriers and 2 unaffecteds, identifying the most likely candidate causal variant as a large insertion in the region of exon 5 of FAM161A. Subsequent Sanger-sequencing of this region in 29 affecteds, 10 obligate carriers and 41 unaffecteds identified a ~230bp insertion containing a 132bp short interspersed nuclear element (SINE), near the splice acceptor site of exon 5. As reported by Downs and Mellersch (2014), ""Analysis of mRNA from an affected dog revealed that the SINE causes exon skipping, resulting in a frame shift, leading to a downstream premature termination codon and possibly a truncated protein product."" " From a GWAS conducted on 22 affected and 10 control Tibetan Spaniels, each genotyped with an Illumina SNP20 BeadChip (yielding 15,674 informative SNPs), Downs and Mellersch (2014) mapped this disorder to a 3.8Mb candidate region on chromosome CFA10. 9615
OMIA:001482 "Using the comparative positional candidate gene approach (based on similarities of the bovine clinical signs with the homologous human disorder, and the mapping results mentioned above), Houweling et al. (2006; Biochim Biophys Acta 1762:890-7) sequenced CLN5 genomic DNA and cDNA from affected and normal Devon cattle, identifying the causal mutation as a ""single base duplication in exon 4 of bovine CLN5 (c.662dupG) . . . . This duplication results in a frameshift, predicted to introduce a premature termination codon six amino acids downstream of the duplication site resulting in the loss of 132 C-terminal amino acids"". " Houweling et al. (2006; Cytogenet Genome Res 115:5-6) used a radiation hybrid panel to physically map the bovine CLN5 gene to chromosome BTA21, which is homologous with the location of human CLN5 on HSA13q21–q23. 9913
OMIA:001820 "Target-enriched deep sequencing of the 1.8Mb candidate region (see Mapping section) and checking identified mutations in various samples of dogs eventually enabled Forman et al. (2013) to claim ""a missense mutation ([c.344G>A;] p.Cys115Tyr) in the gene encoding the large subunit of calcium dependent cysteine protease, μ-calpain (CAPN1)"" as ""a provocative candidate for the cause of SCA in the PRT [Parson Russell Terrier] and a novel potential cause of ataxia in humans.""" "By conducting a GWAS on 16 affected and 16 control Parson Russell Terriers, each genotyped with the Illumina CanineHD (yielding 126,225 informative SNPs), Forman et al. (2013) mapped this disorder to a single peak on chromosome CFA18. Homozygosity mapping defined this as the 1.8 Mb region ""chr18:53,533,360–55,418,743"", which contains 91 genes. Subsequent to the discovery in dogs, similar CAPN1 variants were identified in human patients with autosomal recessive hereditary spastic paraplegia and Capn1 knock-out mice were also shown to have a comparable phenotype. " 9615
OMIA:000735 "By ""sequencing the most physiologically relevant gene from [the candidate region on EC12, namely] damage specific DNA binding protein 2 (DDB2)"", Bellone et al. (2017) ""identified a missense mutation (c.1013 C > T p.Thr338Met) that was strongly [but not completely] associated with limbal SCC""." A GWAS conducted by Bellone et al. (2017) identified a 1.5Mb candidate region on chromosome EC12. 9796
OMIA:001986 "Noting that the candidate region on SSC10 includes the Artemis gene (DCLRE1C), which encodes a DNA repair enzyme, mutations in which cause the same disorder in humans and mice, Waide et al. (2015) sequenced the cDNA and some intronic regions of this positional candidate gene, revealing ""a splice donor site mutation in intron 8 (g.51578763 G→A)"" (which leads to the deletion of exon 8, and, consequently, ""a protein missing 47 aa of the predicted full-length 712-aa Artemis protein""), and ""a G→A nonsense point mutation at g.51584489 that changes the tryptophan amino acid codon at position 267 to a stop codon"". Waide et al. (2015) provided strong evidence that homozygosity for either mutation or compound heterozygosity for both mutations causes this disorder." "By conducting a GWAS on ""six carrier parents, 20 SCID affected piglets, 50 unaffected littermates of the SCID piglets, and 96 ancestors of these animals"", each genotyped with more than 60,000 SNPs via the Illumina porcine SNP60 chip, Waide et al. (2015) mapped this disorder to a 5.6Mb region of chromosome SSC10." 9825